Pharma-informatics system

ABSTRACT

An apparatus that includes a partial power source including a first material and a second material, the partial power source configured to generate, upon contact with a conducting medium, a potential difference between the first material and the second material to provide power to a control device, and generate, using the first material and the second material, a current flow within the conducting medium, the current flow including information encoded based on a variable conductance between the first material and the second material.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/793,374, filed on Feb. 18, 2020, which is a continuation of U.S.application Ser. No. 15/788,968, filed on Oct. 20, 2017, now U.S. Pat.No. 10,610,128, which is a continuation of U.S. application Ser. No.14/699,681, filed on Apr. 29, 2015, which is a continuation of U.S.application Ser. No. 14/596,056, filed on Jan. 13, 2015, now U.S. Pat.No. 9,681,842, which is a continuation of U.S. application Ser. No.12/949,720, filed on Nov. 18, 2010, now U.S. Pat. No. 9,119,554, whichis a continuation of U.S. application Ser. No. 11/912,475, filed on Jun.23, 2008, now U.S. Pat. No. 8,847,766, which is the U.S. National Stageentry of International Application No. PCT/US2006/016370, filed on Apr.28, 2006, which, pursuant to 35 U.S.C. § 119(e), claims priority to thefiling dates of: U.S. Provisional Patent Application Ser. No. 60/676,145filed Apr. 28, 2005; U.S. Provisional Patent Application Ser. No.60/694,078 filed Jun. 24, 2005; U.S. Provisional Patent Application Ser.No. 60/713,680 filed Sep. 1, 2005, and U.S. Provisional PatentApplication Ser. No. 60/790,335 filed Apr. 7, 2006 and entitled“Pharma-Informatics System”; the disclosures of which are hereinincorporated by reference.

BACKGROUND

The present Invention relates generally to medical apparatus andmethods. More specifically, the present invention relates to apparatusand methods for automatic identification of ingestion or other actual,physical administration of a pharmaceutical material.

Prescription medications are effective remedies for many patients whentaken properly, e.g., according to instructions. However, studies haveshown that, on average, about 50% of patients do not comply withprescribed medication regimens. A low rate of compliance with medicationregimens results in a large number of hospitalizations and admissions tonursing homes every year. In the United States alone, it has recentlybeen estimated that the cost to the resulting from patientnon-compliance is reaching $100 billion annually.

Consequently, various methods and apparatus have been made available toimprove patient compliance with prescribed regimens in efforts toimprove patient health. To date, many different types of “smart”packaging devices have been developed. In some cases, such devicesautomatically dispense the appropriate pill. In other cases, there areelectronic controls that detect and record when the pill is taken out ofthe box.

While devices and protocols have been developed for improving patientcompliance, there is continued interest in the development of new waysof monitoring patient compliance.

SUMMARY

The present invention allows, for the first time, the specificidentification of pharmaceutical pills and other types of pharmaceuticaldelivery systems, such as skin diffusion patches, so that the actual,physical delivery of the pharmaceutical into the body can beautomatically detected and this information stored. Because theinventive automatic reporting of physical drug administration does notrequire patient or clinician input, it avoids many of the inaccuracieswhich introduce uncertainty in current drug administration monitoringsystems. These inventive features are particularly critical when apatient's compliance or mental capacity is a consideration, such as inthe administration of psychotropic drugs. The present invention alsoallows for the identification of sources of illicit drugs for lawenforcement purposes.

The present invention allows, for the first time, the specificidentification of pharmaceutical pills and other types of pharmaceuticaldelivery systems, such as skin diffusion patches, so that the actual,physical delivery of the pharmaceutical into the body can beautomatically detected and this information stored. Because theinventive automatic reporting of physical drug administration does notrequire patient or clinician input, it avoids many of the inaccuracieswhich introduce uncertainty in current drug administration monitoringsystems. These inventive features are particularly critical when apatient's compliance or mental capacity is a consideration, such as inthe administration of psychotropic drugs. The present invention alsoallows for the identification of sources of illicit drugs for lawenforcement purposes.

Embodiments of the invention include compositions having: an activeagent; an identifier and a pharmaceutically acceptable carrier. In oneembodiment of the present invention, an ingestible pill is madeidentifiable by providing an electronic microchip as part of the pillstructure. In some aspects, the electronic microchip is completelyencased within the pill. In this embodiment, the pill broadcasts asignal when it is dissolved in an ionic solution such as stomach fluids.The broadcasted signal is received by another device, e.g., a receiver,either inside or near the body. In turn, the receiver then records thatthe pill has in fact reached the stomach and is in the process of beingdissolved.

In certain of these embodiments, the signal is an oscillating signalwhich is picked up by an implanted or topically applied receiver. Theimplant has one or two electrode(s) that sense the varying signal. Theimplant is configured so that it can identify the code and record that aspecific pill has been ingested at a specific time.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 provides a diagrammatic, exemplary representation of the pillembodiment of the present invention.

FIGS. 2A and 2B provide a more detailed view of the pill compositionshown in FIG. 1

FIGS. 3A to 3E provide views of different embodiments of signalgeneration elements of the invention.

FIG. 4 shows diagrammatically the effects of the pill ingestion wheresome of the pill has eroded away.

FIG. 5 provides a similar arrangement to FIG. 4, with a coil rather thantwo electrodes as the output.

FIGS. 6A to 6D provide detail of certain implementations of electroniccircuits of various embodiments of the invention.

FIG. 7 provides an oscillator and a counter implementation according toan embodiment of the invention.

FIG. 8 is an additional embodiment of an oscillator where V controlmodulates the amount of voltage driving the oscillator.

FIG. 9 is an additional embodiment with a simple trickle or asynchronouscounter.

FIG. 10 provides a schematic representation of a three terminal,monopole signal generation element according to an embodiment of theinvention.

FIGS. 11A to 13B are diagrams showing a method for fabricating anidentifier according to an embodiment of the invention.

FIG. 14 shows the multiplexer and the addressing system.

FIG. 15 shows a detail of the 4 bit mux of the system shown in FIG. 14.

FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux.

FIG. 17 is an additional monopole embodiment of a signal generationelement.

FIG. 18A is an exemplary schematic diagram of a signal-transmissiondriver circuit that transmits a signal at a fixed frequency, inaccordance with one embodiment of the present invention.

FIG. 18B1-18B2 provides an exemplary schematic diagram of a receivercircuit, in accordance with one embodiment of the present invention.

FIG. 19 shows one exemplary split (i.e., segmented) battery design, inaccordance with one embodiment of the present invention.

FIG. 20 shows one exemplary design of the driver circuit that uses splitbattery electrodes for transmission, in accordance with one embodimentof the present invention.

FIG. 21 shows one exemplary split battery design with a split cathode,in accordance with one embodiment of the present invention.

FIG. 22 shows one exemplary design where the battery electrodes for thedriver circuit are coupled to the driver circuit via two external wires,in accordance with one embodiment of the present invention.

FIG. 23 shows the principle of an experiment with a split batteryconfiguration.

FIG. 24 shows the performance of a pair of split batteries.

DETAILED DESCRIPTION

The present invention provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.By example, when used in concert with other medical sensing devices,correlation between drug delivery, batch and dosage can be correlated toa physiological response. In this manner, optimal pharma-therapeuticregimens may be formulated by the clinician. By example, cardiacstimulating drugs can be titrated to the most appropriate dosages,minimizing side effects such as cardiac muscle exhaustion and reboundeffects among others, and optimizing both dosage and timing for each,individual patient.

Assessment of a range of alternate medications is made possible by thepresent invention without resort to awaiting overt clinical sequel oftreatment, many of which can be seriously adverse. By example, positiveeffects would be quickly ascertainable without being obscured by morerandom factors. Negative responses, such as changes in blood pressure,would become clearly evident as drug related or independent abovebackground physiologic variation.

The ability to document the ingestion of a drug or other actual exposureof the body to a medication has many important clinical applications. Inthe simplest form, this technique provides accurate data of when a pillhas been taken and which pill has been taken. This allows the precisedetermination of which pill was taken at a specific point in time. Suchmonitoring capability assures patients are taking the prescribedmedication correctly. This information avoids the potential for overprescription of medications that are not actually being taken. Byexample, if pain killers are intended to be administered to a patient,it is possible to verify that the patient did in fact take those painkillers in a certain period of time. This is an important tool inlimiting the illicit sale of unconsumed drugs to an unintended party. Inthe case of cardio vascular pills, the clinician or care giver is ableto verify that the amount of the drug was taken has been taken atapproximately the right point and time. Thus, the true efficacy of thedrug can be accurately evaluated. Proper administration and patientcompliance is especially critical in Alzheimer's, psychiatric, andalcohol aversion drugs, and in the treatment of rest home residents. Inthe case of accidental and other overdoses situations, the interveningclinician will be able to discern how far the ingestion has proceeded,and how many pills are involved.

In one clinical arena, the present invention allows, in concert withother sensing device developed by some of the present inventors, themeasurement and assessment of the cardiac response to those medications.These co-employed sensing devices can be those enumerated below, amongothers. Other sensing technology developed by some of the presentinventors allows measurement of heart health and cardiac efficiency.Using these tools in concert with the present inventive device, theclinician will be able to compare the response of the heart and body tothe administered pharmaceutical.

The data provided by the present invention can optionally be recordedover time. The recording system records synchrony or conduction velocityof a signal going through cardiac tissue and how that is mediated by thepresence of a certain medication. This unique data is made possible bythe present invention since it can determine electronically exactly whenthe pill or other medication was being absorbed into the body.

From this innovative data, the present invention provides the clinicianan accurate dose response curve showing the response to that medicationand the timing of the digestion of the pill. Such innovative data hasmany applications. For instance, the clinician now has the ability todetermine which patients have no response to the medicine in the pill.In a study situation, such patients can be removed from a study or atest of the clinical utility of a certain medication. This provides thatonly people who have a beneficial response to a certain medication areretained in the trail. This feature will improve the efficacy ofmedications and to reduce the amount of medications that people takethat are not being useful. It may also be used in trials to determinewhich patients actually consumed the medicine, and which did not.

In more standard clinical environments, this unique data allows carefulselection and titration of drug administration without resort to moreovert physical symptoms to ascertain contraindications, efficacy, andoptimal dosage levels.

The present invention provides a record for emergency room techniciansor doctors when a patient is admitted to a hospital so that thepatient's status can be accurately ascertained. Dosage events within thelast hour or day prior to admission, and the identity of the lastmedication, will be immediately available.

The clinician obtains this information through simple interrogation ofthe implanted or portable device. This device would tell them withoutany uncertainty what pills have been taken. As the inventive technologybecomes more wide spread, this data will become more regularlyavailable. The present inventive microchips described below aresufficiently inexpensive when put into standard production that most orall pharmaceuticals will be fitted with them as a matter of course.

In other embodiments of the inventive microchips, the chips can befitted with coils, susceptible of interrogation without being dissolvedin the body. This is accomplished by transmitting RF energy into thecoil in such a way that the inquirer will be apprised of the presenceand identity of a pill before it is ingested.

In an additional embodiment of the present invention, a “smart box” isprovided that can interrogate each pill and ascertain its address. Thebox can write a distinctive product number or product code so that everysingle pill ever made is provided with a unique identifier. Fuses, forexample, may be selectively destroyed so the addresses may be detectedelectrically or optically. Particularly in the case of controlledsubstances, such as a narcotic, this will be important in limiting theillegal used of previously legitimate medicines. The present inventionmakes it possible to identify precisely who bought such a pill from theauthorized pharmacist. This use of the present invention will rein inthe number of illicit uses of controlled substances on the market place.

In further describing the invention in greater detail, embodiments ofthe compositions are reviewed first, followed by a discussion of systemsincluding the subject compositions, methods of using the subjectcompositions and systems and various illustrative applications in whichthe compositions and methods find use. Also reviewed in greater detailbelow are kits that include the subject compositions.

Compositions

Embodiments of the invention include active agent compositions having anidentifier stably associated therewith. In certain embodiments, thecompositions are disrupted upon administration to a subject. As such, incertain embodiments, the compositions are physically broken, e.g.,dissolved, degraded, eroded, etc., following delivery to a body, e.g.,via ingestion, injection, etc. The compositions of these embodiments aredistinguished from devices that are configured to be ingested andsurvive transit through the gastrointestinal tract substantially, if notcompletely, intact. While the compositions of these embodiments arethemselves disrupted upon administration, components of the composition,e.g., the identifier, may survive transit of the gastrointestinal tract,e.g., as described in greater detail below.

In certain embodiments, the compositions include an active agent/carriercomponent and an identifier. Each of these different components isreviewed separately in greater detail below.

Active Agent/Carrier Component

The subject compositions include an active agent/carrier component. By“active agent/carrier component” is meant a composition, which may be asolid or fluid (e.g., liquid), which has an amount of active agent,e.g., a dosage, present in a pharmaceutically acceptable carrier. Theactive agent/carrier component may be referred to as a “dosageformulation.”

Active Agent

“Active agent” includes any compound or mixture of compounds whichproduces a physiological result, e.g., a beneficial or useful result,upon contact with a living organism, e.g., a mammal, such as a human.Active agents are distinguishable from such components as vehicles,carriers, diluents, lubricants, binders and other formulating aids, andencapsulating or otherwise protective components. The active agent maybe any molecule, as well as binding portion or fragment thereof, that iscapable of modulating a biological process in a living subject. Incertain embodiments, the active agent may be a substance used in thediagnosis, treatment, or prevention of a disease or as a component of amedication. In certain embodiments, the active agent may be a chemicalsubstance, such as a narcotic or hallucinogen, which affects the centralnervous system and causes changes in behavior.

The active agent (i.e., drug) is capable of interacting with a target ina living subject. The target may be a number of different types ofnaturally occurring structures, where targets of interest include bothintracellular and extracellular targets. Such targets may be proteins,phospholipids, nucleic acids and the like, where proteins are ofparticular interest. Specific proteinaceous targets of interest include,without limitation, enzymes, e.g. kinases, phosphatases, reductases,cyclooxygenases, proteases and the like, targets comprising domainsinvolved in protein-protein interactions, such as the SH2, SH3, PTB andPDZ domains, structural proteins, e.g. actin, tubulin, etc., membranereceptors, immunoglobulins, e.g. IgE, cell adhesion receptors, such asintegrins, etc., ion channels, transmembrane pumps, transcriptionfactors, signaling proteins, and the like.

The active agent (i.e., drug) may include one or more functional groupsnecessary for structural interaction with the target, e.g., groupsnecessary for hydrophobic, hydrophilic, electrostatic or even covalentinteractions, depending on the particular drug and its intended target.Where the target is a protein, the drug moiety may include functionalgroups necessary for structural interaction with proteins, such ashydrogen bonding, hydrophobic-hydrophobic interactions, electrostaticinteractions, etc., and may include at least an amine, amide,sulfhydryl, carbonyl, hydroxyl or carboxyl group, such as at least twoof the functional chemical groups.

Drugs of interest may include cyclical carbon or heterocyclic structuresand/or aromatic or polyaromatic structures substituted with one or moreof the above functional groups. Also of interest as drug moieties arestructures found among biomolecules, including peptides, saccharides,fatty acids, steroids, purines, pyrimidines, derivatives, structuralanalogs or combinations thereof. Such compounds may be screened toidentify those of interest, where a variety of different screeningprotocols are known in the art.

The drugs may be derived from a naturally occurring or syntheticcompound that may be obtained from a wide variety of sources, includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including the preparation ofrandomized oligonucleotides and oligopeptides. Alternatively, librariesof natural compounds in the form of bacterial, fungal, plant and animalextracts are available or readily produced. Additionally, natural orsynthetically produced libraries and compounds are readily modifiedthrough conventional chemical, physical and biochemical means, and maybe used to produce combinatorial libraries. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification, etc. to producestructural analogs.

As such, the drug may be obtained from a library of naturally occurringor synthetic molecules, including a library of compounds producedthrough combinatorial means, i.e., a compound diversity combinatoriallibrary. When obtained from such libraries, the drug moiety employedwill have demonstrated some desirable activity in an appropriatescreening assay for the activity. Combinatorial libraries, as well asmethods for producing and screening such libraries, are known in the artand described in: U.S. Pat. Nos. 5,741,713; 5,734,018; 5,731,423;5,721,099; 5,708,153; 5,698,673; 5,688,997; 5,688,696; 5,684,711;5,641,862; 5,639,603; 5,593,853; 5,574,656; 5,571,698; 5,565,324;5,549,974; 5,545,568; 5,541,061; 5,525,735; 5,463,564; 5,440,016;5,438,119; 5,223,409, the disclosures of which are herein incorporatedby reference.

Broad categories of active agents of interest include, but are notlimited to: cardiovascular agents; pain-relief agents, e.g., analgesics,anesthetics, anti-inflammatory agents, etc.; nerve-acting agents;chemotherapeutic (e.g., anti-neoplastic) agents; etc.

In certain embodiments, the active agent is a cardiovascular agent,i.e., an agent employed in the treatment of cardiovascular or heartconditions. In certain embodiments, the active agent is a cardiovascularagent, i.e., an agent employed in the treatment of cardiovascular orheart conditions. Cardiovascular agents of interest include, but are notlimited to: cardioprotective agents, e.g., Zinecard (dexrazoxane); bloodmodifiers, including anticoagulants (e.g., coumadin (warfarin sodium),fragmin (dalteparin sodium), heparin, innohep (tinzaparin sodium),lovenox (enoxaparin sodium), orgaran (danaparoid sodium)) antiplateletagents (e.g., aggrasta (tirofiban hydrochloride), aggrenox(aspirin/extended release dipyridamole), agrylin (anagrelidehydrochloride), ecotrin (acetylsalicylic acid), folan (epoprostenolsodium), halfprin (enteric coated aspirin), integrlilin (eptifibatide),persantine (dipyridamole USP), plavix (clopidogrel bisulfate), pletal(cilostazol), reopro (abciximab), ticlid (ticlopidine hydrochloride)),thrombolytic agents (activase (alteplase), retavase (reteplase),streptase (streptokinase)); adrenergic blockers, such as cardura(doxazosin mesylate), dibenzyline (phenoxybenzamine hydrochloride),hytrin (terazosin hydrochloride), minipress (prazosin hydrochloride),minizide (prazosin hydrochloride/polythiazide); adrenergic stimulants,such as aldoclor (methyldopa—chlorothiazide), aldomet (methyldopa,methyldopate HCl), aldoril (methyldopa—hydrochlorothiazide), catapres(clonidine hydrochloride USP, clonidine), clorpres (clonidinehydrochloride and chlorthalidone), combipres (clonidinehydrochloride/chlorthalidone), tenex (guanfacine hydrochloride);alpha/bet adrenergic blockers, such as coreg (carvedilol), normodyne(labetalol hydrochloride); angiotensin converting enzyme (ACE)inhibitors, such as accupril (quinapril hydrochloride), aceon(perindopril erbumine), altace (ramipril), captopril, lotensin(benazepril hydrochloride), mavik (trandolapril), monopril (fosinoprilsodium tablets), prinivil (lisinopril), univasc (moexiprilhydrochloride), vasotec (enalaprilat, enalapril maleate), zestril(lisinopril); angiotensin converting enzyme (ACE) inhibitors withcalcium channel blockers, such as lexxel (enalapril maleate—felodipineER), lotrel (amlodipine and benazepril hydrochloride), tarka(trandolapril/verapamil hydrochloride ER); angiotensin converting enzyme(ACE) inhibitors with diuretics, such as accuretic (quinaprilHCl/hydroclorothiazide), lotensin (benazepril hydrochloride andhydrochlorothiazide USP), prinizide (lisinopril-hydrochlorothiazide),uniretic (moexipril hydrochloride/hydrochlorothiazide), vaseretic(enalapril maleate—hydrochlorothiazide), zestoretic (lisinopril andhydrochlorothiazide); angiotensin II receptor antagonists, such asatacand (candesartan cilexetil), avapro (irbesartan), cozaar (losartanpotassium), diovan (valsartan), micardis (telmisartan), teveten(eprosartan mesylate); angiotensin II receptor antagonists withdiuretics, such as avalide (irbesartan—hydrochlorothiazide), diovan(valsartan and hydrochlorothiazide), hyzaar (losartanpotassium—hydrochlorothiazide); antiarrhythmics, such as Group I (e.g.,mexitil (mexiletine hydrochloride, USP), norpace (disopyramidephosphate), procanbid (procainamide hydrochloride), quinaglute(quinidine gluconate), quinidex (quinidine sulfate), quinidine(quinidine gluconate injection, USP), rythmol (propafenonehydrochloride), tambocor (flecainide acetate), tonocard (tocainideHCl)), Group II (e.g., betapace (sotalol HCl), brevibloc (esmololhydrochloride), inderal (propranolol hydrochloride), sectral (acebutololhydrochloride)), Group III (e.g., betapace (sotalol HCl), cordarone(amiodarone hydrochloride), corvert (ibutilide fumarate injection),pacerone (amiodarone HCl), tikosyn (dofetilide)), Group IV (e.g., calan(verapamil hydrochloride), cardizem (diltiazem HCl), as well asadenocard (adenosine), lanoxicaps (digoxin), lanoxin (digoxin));antilipemic acids, including bile acid sequestrants (e.g., colestid(micronized colestipol hydrochloride), welchol (colesevelamhydrochloride)), fibric acid derivatives (e.g., atromid (clofibrate),lopid (gemfibrozal tablets, USP), tricor (fenofibrate capsules)),HMG-CoA reductase inhibitors (e.g., baycol (cerivastatin sodiumtablets), lescol (fluvastatin sodium), lipitor (atorvastatin calcium),mevacor (lovastatin), pravachol (pravastatin sodium), zocor(simvastatin)), Nicotinic Acid (e.g., Niaspan (niacin extended releasetablets)); beta adrenergic blocking agents, e.g., betapace (sotalolHCl), blocadren (timolol maleate), brevibloc (esmolol hydrochloride),cartrol (carteolol hydrochloride), inderal (propranolol hydrochloride),kerlone (betaxolol hydrochloride), nadolol, sectral (acebutololhydrochloride), tenormin (atenolol), toprol (metoprolol succinate),zebeta (bisoprolol fumarate); beta adrenergic blocking agents withdiuretics, e.g., corzide (nadolol and bendroflumethiazide tablets),inderide (propranolol hydrochloride and hydroclorothiazide), tenoretic(atenolol and chlorthalidone), timolide (timololmaleate—hydrochlorothiazide), ziac (bisoprolol fumarate andhydrochloro-thiazide); calcium channel blockers, e.g., adalat(nifedipine), calan (verapamil hydrochloride), cardene (nicardipinehydrochloride), cardizem (diltiazem HCl), covera (verapamilhydrochloride), isoptin (verapamil hydrochloride), nimotop (nimodipine),norvasc (amlodipine besylate), plendil (felodipine), procardia(nifedipine), sular (nisoldipine), tiazac (diltiazem hydrochloride),vascor (bepridil hydrochloride), verelan (verapamil hydrochloride);diuretics, including carbonic anhydrase inhibitors (e.g., daranide(dichlorphenamide)), combination diuretics (e.g., aldactazide(spironolactone with hydrochlorothiazide), dyazide (triamterene andhydrochlorothiazide), maxzide (triamterene and hydrochlorothiazide),moduretic (amiloride HCl—hydrochlorothiazide)), loop diuretics (demadex(torsemide), edecrin (ethacrynic acid, ethacrynate sodium), furosemide),potassium-sparing diuretics (aldactone (spironolactone), dyrenium(triamterene), midamor (amiloride HCl)), thiazides & related diuretics(e.g., diucardin (hydroflumethiazide), diuril (chlorothiazide,chlorothiazide sodium), enduron (methyclothiazide), hydrodiurilhydrochlorothiazide), indapamide, microzide (hydrochlorothiazide) mykrox(metolazone tablets), renese (polythi-azide), thalitone (chlorthalidone,USP), zaroxolyn (metolazone)); inotropic agents, e.g., digitek(digoxin), dobutrex (dobutamine), lanoxicaps (digoxin), lanoxin(digoxin), primacor (milrinone lactate); activase (alteplaserecombinant); adrenaline chloride (epinephrine injection, USP); demser(metyrosine), inversine (mecamylamine HCl), reopro (abciximab), retavase(reteplase), streptase (streptokinase), tnkase (tenecteplase);vasodilators, including coronary vasodilators (e.g., imdur (isosorbidemononitrate), ismo (isosorbide mononitrate), isordil (isosorbidedinitrate), nitrodur (nitroglycerin), nitrolingual (nitroglycerinlingual spray), nitrostat (nitroglycerin tablets, USP), sorbitrate(isosorbide dinitrate)), peripheral vasodilators & combinations (e.g.,corlopam (fenoldopam mesylate), fiolan (epoprostenol sodium), primacor(milrinone lactate)), vasopressors, e.g., aramine (metaraminolbitartrate), epipen (EpiPen 0.3 mg brand of epinephrine auto injector,EpiPen Jr. 0.15 mg brand of epinephrine auto injector), proamatine(midodrine hydrochloride); etc.

In certain embodiments, specific drugs of interest include, but are notlimited to: psychopharmacological agents, such as (1) central nervoussystem depressants, e.g. general anesthetics (barbiturates,benzodiazepines, steroids, cyclohexanone derivatives, and miscellaneousagents), sedative-hypnotics (benzodiazepines, barbiturates,piperidinediones and triones, quinazoline derivatives, carbamates,aldehydes and derivatives, amides, acyclic ureides, benzazepines andrelated drugs, phenothiazines, etc.), central voluntary muscle tonemodifying drugs (anticonvulsants, such as hydantoins, barbiturates,oxazolidinediones, succinimides, acylureides, glutarimides,benzodiazepines, secondary and tertiary alcohols, dibenzazepinederivatives, valproic acid and derivatives, GABA analogs, etc.),analgesics (morphine and derivatives, oripavine derivatives, morphinanderivatives, phenylpiperidines, 2,6-methane-3-benzazocaine derivatives,diphenylpropylamines and isosteres, salicylates, p-aminophenolderivatives, 5-pyrazolone derivatives, arylacetic acid derivatives,fenamates and isosteres, etc.) and antiemetics (anticholinergics,antihistamines, antidopaminergics, etc.), (2) central nervous systemstimulants, e.g. analeptics (respiratory stimulants, convulsantstimulants, psychomotor stimulants), narcotic antagonists (morphinederivatives, oripavine derivatives, 2,6-methane-3-benzoxacinederivatives, morphinan derivatives) nootropics, (3)psychopharmacologicals, e.g. anxiolytic sedatives (benzodiazepines,propanediol carbamates) antipsychotics (phenothiazine derivatives,thioxanthine derivatives, other tricyclic compounds, butyrophenonederivatives and isosteres, diphenylbutylamine derivatives, substitutedbenzamides, arylpiperazine derivatives, indole derivatives, etc.),antidepressants (tricyclic compounds, MAO inhibitors, etc.), (4)respiratory tract drugs, e.g. central antitussives (opium alkaloids andtheir derivatives);

pharmacodynamic agents, such as (1) peripheral nervous system drugs,e.g. local anesthetics (ester derivatives, amide derivatives), (2) drugsacting at synaptic or neuroeffector junctional sites, e.g. cholinergicagents, cholinergic blocking agents, neuromuscular blocking agents,adrenergic agents, antiadrenergic agents, (3) smooth muscle activedrugs, e.g. spasmolytics (anticholinergics, musculotropic spasmolytics),vasodilators, smooth muscle stimulants, (4) histamines andantihistamines, e.g. histamine and derivative thereof (betazole),antihistamines (H1-antagonists, H2-antagonists), histamine metabolismdrugs, (5) cardiovascular drugs, e.g. cardiotonics (plant extracts,butenolides, pentadienolids, alkaloids from erythrophleum species,ionophores,—adrenoceptor stimulants, etc), antiarrhythmic drugs,antihypertensive agents, antilipidemic agents (clofibric acidderivatives, nicotinic acid derivatives, hormones and analogs,antibiotics, salicylic acid and derivatives), antivaricose drugs,hemostyptics, (6) blood and hemopoietic system drugs, e.g. antianemiadrugs, blood coagulation drugs (hemostatics, anticoagulants,antithrombotics, thrombolytics, blood proteins and their fractions), (7)gastrointestinal tract drugs, e.g. digestants (stomachics, choleretics),antiulcer drugs, antidiarrheal agents, (8) locally acting drugs;

chemotherapeutic agents, such as (1) anti-infective agents, e.g.ectoparasiticides (chlorinated hydrocarbons, pyrethins, sulfuratedcompounds), anthelmintics, antiprotozoal agents, antimalarial agents,antiamebic agents, antileiscmanial drugs, antitrichomonal agents,antitrypanosomal agents, sulfonamides, antimycobacterial drugs,antiviral chemotherapeutics, etc., and (2) cytostatics, i.e.antineoplastic agents or cytotoxic drugs, such as alkylating agents,e.g. Mechlorethamine hydrochloride (Nitrogen Mustard, Mustargen, HN2),Cyclophosphamide (Cytovan, Endoxana), Ifosfamide (IFEX), Chlorambucil(Leukeran), Melphalan (Phenylalanine Mustard, L-sarcolysin, Alkeran,L-PAM), Busulfan (Myleran), Thiotepa (Triethylenethiophosphoramide),Carmustine (BiCNU, BCNU), Lomustine (CeeNU, CCNU), Streptozocin(Zanosar) and the like; plant alkaloids, e.g. Vincristine (Oncovin),Vinblastine (Velban, Velbe), Paclitaxel (Taxol), and the like;antimetabolites, e.g. Methotrexate (MTX), Mercaptopurine (Purinethol,6-MP), Thioguanine (6-TG), Fluorouracil (5-FU), Cytarabine (Cytosar-U,Ara-C), Azacitidine (Mylosar, 5-AZA) and the like; antibiotics, e.g.Dactinomycin (Actinomycin D, Cosmegen), Doxorubicin (Adriamycin),Daunorubicin (duanomycin, Cerubidine), Idarubicin (Idamycin), Bleomycin(Blenoxane), Picamycin (Mithramycin, Mithracin), Mitomycin (Mutamycin)and the like, and other anticellular proliferative agents, e.g.Hydroxyurea (Hydrea), Procarbazine (Mutalane), Dacarbazine (DTIC-Dome),Cisplatin (Platinol) Carboplatin (Paraplatin), Asparaginase (Elspar)Etoposide (VePesid, VP-16-213), Amsarcrine (AMSA, m-AMSA), Mitotane(Lysodren), Mitoxantrone (Novatrone), and the like;

antibiotics, such as: aminoglycosides, e.g. amikacin, apramycin,arbekacin, bambermycins, butirosin, dibekacin, dihydrostreptomycin,fortimicin, gentamicin, isepamicin, kanamycin, micronomcin, neomycin,netilmicin, paromycin, ribostamycin, sisomicin, spectinomycin,streptomycin, tobramycin, trospectomycin; amphenicols, e.g.azidamfenicol, chloramphenicol, florfenicol, and theimaphenicol;ansamycins, e.g. rifamide, rifampin, rifamycin, rifapentine, rifaximin;b-lactams, e.g. carbacephems, carbapenems, cephalosporins, cehpamycins,monobactams, oxaphems, penicillins; lincosamides, e.g. clinamycin,lincomycin; macrolides, e.g. clarithromycin, dirthromycin, erythromycin,etc.; polypeptides, e.g. amphomycin, bacitracin, capreomycin, etc.;tetracyclines, e.g. apicycline, chlortetracycline, clomocycline, etc.;synthetic antibacterial agents, such as 2,4-diaminopyrimidines,nitrofurans, quinolones and analogs thereof, sulfonamides, sulfones;

antifungal agents, such as: polyenes, e.g. amphotericin B, candicidin,dermostatin, filipin, fungichromin, hachimycin, hamycin, lucensomycin,mepartricin, natamycin, nystatin, pecilocin, perimycin; syntheticantifungals, such as allylamines, e.g. butenafine, naftifine,terbinafine; imidazoles, e.g. bifonazole, butoconazole, chlordantoin,chlormidazole, etc., thiocarbamates, e.g. tolciclate, triazoles, e.g.fluconazole, itraconazole, terconazole;

anthelmintics, such as: arecoline, aspidin, aspidinol, dichlorophene,embelin, kosin, napthalene, niclosamide, pelletierine, quinacrine,alantolactone, amocarzine, amoscanate, ascaridole, bephenium,bitoscanate, carbon tetrachloride, carvacrol, cyclobendazole,diethylcarbamazine, etc.;

antimalarials, such as: acedapsone, amodiaquin, arteether, artemether,artemisinin, artesunate, atovaquone, bebeerine, berberine, chirata,chlorguanide, chloroquine, chlorprogaunil, cinchona, cinchonidine,cinchonine, cycloguanil, gentiopicrin, halofantrine, hydroxychloroquine,mefloquine hydrochloride, 3-methylarsacetin, pamaquine, plasmocid,primaquine, pyrimethamine, quinacrine, quinidine, quinine, quinocide,quinoline, dibasic sodium arsenate;

antiprotozoan agents, such as: acranil, tinidazole, ipronidazole,ethylstibamine, pentamidine, acetarsone, aminitrozole, anisomycin,nifuratel, tinidazole, benzidazole, suramin, and the like.

Name brand drugs of interest include, but are not limited to: RezulinÔ,Lovastatin™, Enalapril™, Prozac™, Prilosec™, Lipotor™, Claritin™,Zocor™, Ciprofloxacin™, Viagra™, Crixivan™, Ritalin™, and the like.

Drug compounds of interest are also listed in: Goodman & Gilman's, ThePharmacological Basis of Therapeutics (9th Ed) (Goodman et al. eds)(McGraw-Hill) (1996); and 2001 Physician's Desk Reference.

Specific compounds of interest also include, but are not limited to:

Antineoplastic agents, as disclosed in U.S. Pat. Nos. 5,880,161,5,877,206, 5,786,344, 5,760,041, 5,753,668, 5,698,529, 5,684,004,5,665,715, 5,654,484, 5,624,924, 5,618,813, 5,610,292, 5,597,831,5,530,026, 5,525,633, 5,525,606, 5,512,678, 5,508,277, 5,463,181,5,409,893, 5,358,952, 5,318,965, 5,223,503, 5,214,068, 5,196,424,5,109,024, 5,106,996, 5,101,072, 5,077,404, 5,071,848, 5,066,493,5,019,390, 4,996,229, 4,996,206, 4,970,318, 4,968,800, 4,962,114,4,927,828, 4,892,887, 4,889,859, 4,886,790, 4,882,334, 4,882,333,4,871,746, 4,863,955, 4,849,563, 4,845,216, 4,833,145, 4,824,955,4,785,085, 476,925, 4,684,747, 4,618,685, 4,611,066, 4,550,187,4,550,186, 4,544,501, 4,541,956, 4,532,327, 4,490,540, 4,399,283,4,391,982, 4,383,994, 4,294,763, 4,283,394, 4,246,411, 4,214,089,4,150,231, 4,147,798, 4,056,673, 4,029,661, 4,012,448;

psycopharmacological/psychotropic agents, as disclosed in U.S. Pat. Nos.5,192,799, 5,036,070, 4,778,800, 4,753,951, 4,590,180, 4,690,930,4,645,773, 4,427,694, 4,424,202, 4,440,781, 5,686,482, 5,478,828,5,461,062, 5,387,593, 5,387,586, 5,256,664, 5,192,799, 5,120,733,5,036,070, 4,977,167, 4,904,663, 4,788,188, 4,778,800, 4,753,951,4,690,930, 4,645,773, 4,631,285, 4,617,314, 4,613,600, 4,590,180,4,560,684, 4,548,938, 4,529,727, 4,459,306, 4,443,451, 4,440,781,4,427,694, 4,424,202, 4,397,853, 4,358,451, 4,324,787, 4,314,081,4,313,896, 4,294,828, 4,277,476, 4,267,328, 4,264,499, 4,231,930,4,194,009, 4,188,388, 4,148,796, 4,128,717, 4,062,858, 4,031,226,4,020,072, 4,018,895, 4,018,779, 4,013,672, 3,994,898, 3,968,125,3,939,152, 3,928,356, 3,880,834, 3,668,210;

cardiovascular agents, as disclosed in U.S. Pat. Nos. 4,966,967,5,661,129, 5,552,411, 5,332,737, 5,389,675, 5,198,449, 5,079,247,4,966,967, 4,874,760, 4,954,526, 5,051,423, 4,888,335, 4,853,391,4,906,634, 4,775,757, 4,727,072, 4,542,160, 4,522,949, 4,524,151,4,525,479, 4,474,804, 4,520,026, 4,520,026, 5,869,478, 5,859,239,5,837,702, 5,807,889, 5,731,322, 5,726,171, 5,723,457, 5,705,523,5,696,111, 5,691,332, 5,679,672, 5,661,129, 5,654,294, 5,646,276,5,637,586, 5,631,251, 5,612,370, 5,612,323, 5,574,037, 5,563,170,5,552,411, 5,552,397, 5,547,966, 5,482,925, 5,457,118, 5,414,017,5,414,013, 5,401,758, 5,393,771, 5,362,902, 5,332,737, 5,310,731,5,260,444, 5,223,516, 5,217,958, 5,208,245, 5,202,330, 5,198,449,5,189,036, 5,185,362, 5,140,031, 5,128,349, 5,116,861, 5,079,247,5,070,099, 5,061,813, 5,055,466, 5,051,423, 5,036,065, 5,026,712,5,011,931, 5,006,542, 4,981,843, 4,977,144, 4,971,984, 4,966,967,4,959,383, 4,954,526, 4,952,692, 4,939,137, 4,906,634, 4,889,866,4,888,335, 4,883,872, 4,883,811, 4,847,379, 4,835,157, 4,824,831,4,780,538, 4,775,757, 4,774,239, 4,771,047, 4,769,371, 4,767,756,4,762,837, 4,753,946, 4,752,616, 4,749,715, 4,738,978, 4,735,962,4,734,426, 4,734,425, 4,734,424, 4,730,052, 4,727,072, 4,721,796,4,707,550, 4,704,382, 4,703,120, 4,681,970, 4,681,882, 4,670,560,4,670,453, 4,668,787, 4,663,337, 4,663,336, 4,661,506, 4,656,267,4,656,185, 4,654,357, 4,654,356, 4,654,355, 4,654,335, 4,652,578,4,652,576, 4,650,874, 4,650,797, 4,649,139, 4,647,585, 4,647,573,4,647,565, 4,647,561, 4,645,836, 4,639,461, 4,638,012, 4,638,011,4,632,931, 4,631,283, 4,628,095, 4,626,548, 4,614,825, 4,611,007,4,611,006, 4,611,005, 4,609,671, 4,608,386, 4,607,049, 4,607,048,4,595,692, 4,593,042, 4,593,029, 4,591,603, 4,588,743, 4,588,742,4,588,741, 4,582,854, 4,575,512, 4,568,762, 4,560,698, 4,556,739,4,556,675, 4,555,571, 4,555,570, 4,555,523, 4,550,120, 4,542,160,4,542,157, 4,542,156, 4,542,155, 4,542,151, 4,537,981, 4,537,904,4,536,514, 4,536,513, 4,533,673, 4,526,901, 4,526,900, 4,525,479,4,524,151, 4,522,949, 4,521,539, 4,520,026, 4,517,188, 4,482,562,4,474,804, 4,474,803, 4,472,411, 4,466,979, 4,463,015, 4,456,617,4,456,616, 4,456,615, 4,418,076, 4,416,896, 4,252,815, 4,220,594,4,190,587, 4,177,280, 4,164,586, 4,151,297, 4,145,443, 4,143,054,4,123,550, 4,083,968, 4,076,834, 4,064,259, 4,064,258, 4,064,257,4,058,620, 4,001,421, 3,993,639, 3,991,057, 3,982,010, 3,980,652,3,968,117, 3,959,296, 3,951,950, 3,933,834, 3,925,369, 3,923,818,3,898,210, 3,897,442, 3,897,441, 3,886,157, 3,883,540, 3,873,715,3,867,383, 3,873,715, 3,867,383, 3,691,216, 3,624,126;

antimicrobial agents as disclosed in U.S. Pat. Nos. 5,902,594,5,874,476, 5,874,436, 5,859,027, 5,856,320, 5,854,242, 5,811,091,5,786,350, 5,783,177, 5,773,469, 5,762,919, 5,753,715, 5,741,526,5,709,870, 5,707,990, 5,696,117, 5,684,042, 5,683,709, 5,656,591,5,643,971, 5,643,950, 5,610,196, 5,608,056, 5,604,262, 5,595,742,5,576,341, 5,554,373, 5,541,233, 5,534,546, 5,534,508, 5,514,715,5,508,417, 5,464,832, 5,428,073, 5,428,016, 5,424,396, 5,399,553,5,391,544, 5,385,902, 5,359,066, 5,356,803, 5,354,862, 5,346,913,5,302,592, 5,288,693, 5,266,567, 5,254,685, 5,252,745, 5,209,930,5,196,441, 5,190,961, 5,175,160, 5,157,051, 5,096,700, 5,093,342,5,089,251, 5,073,570, 5,061,702, 5,037,809, 5,036,077, 5,010,109,4,970,226, 4,916,156, 4,888,434, 4,870,093, 4,855,318, 4,784,991,4,479,953, 4,260,634, 4,055,655, 3,915,889, 4,746,504, 4,686,221,4,599,228, 4,552,882, 4,492,700, 4,489,098, 4,489,085, 4,487,776,4,477,448, 4,474,807, 4,470,994, 4,370,484, 4,337,199, 4,311,709,4,308,283, 4,304,910, 4,233,311, 4,215,131, 4,166,122, 4,141,981,4,130,664, 4,089,977, 4,089,900, 4,069,341, 4,049,665, 4,044,139,4,002,775, 3,991,201, 3,966,968, 3,954,868, 3,936,393, 3,917,476,3,867,548, 3,865,748, 3,867,548, 3,865,748, 3,783,160, 3,764,676,3,764,677;

anti-inflammatory agents as disclosed in U.S. Pat. Nos. 5,872,109,5,837,735, 5,827,837, 5,821,250, 5,814,648, 5,780,026, 5,776,946,5,760,002, 5,750,543, 5,741,798, 5,739,279, 5,733,939, 5,723,481,5,716,967, 5,688,949, 5,686,488, 5,686,471, 5,686,434, 5,684,204,5,684,041, 5,684,031, 5,684,002, 5,677,318, 5,674,891, 5,672,6205,665,752, 5,656,661, 5,635,516, 5,631,283, 5,622,948, 5,618,835,5,607,959, 5,593,980, 5,593,960, 5,580,888, 5,552,424, 5,552,4225,516,764, 5,510,361, 5,508,026, 5,500,417, 5,498,405, 5,494,927:5,476,876 5,472,973 5,470,885, 5,470,842, 5,464,856, 5,464,8495,462,952, 5,459,151, 5,451,686, 5,444,043 5,436,265, 5,432,181,RE034,918, 5,393,756, 5,380,738, 5,376,670, 5,360,811, 5,354,768,5,348,957, 5,347,029, 5,340,815, 5,338,753, 5,324,648, 5,319,099,5,318,971, 5,312,821, 5,302,597, 5,298,633, 5,298,522, 5,298,498,5,290,800, 5,290,788, 5,284,949, 5,280,045, 5,270,319, 5,266,562,5,256,680, 5,250,700, 5,250,552, 5,248,682, 5,244,917, 5,240,929,5,234,939, 5,234,937, 5,232,939, 5,225,571, 5,225,418, 5,220,025,5,212,189, 5,212,172, 5,208,250, 5,204,365, 5,202,350, 5,196,431,5,191,084, 5,187,175, 5,185,326, 5,183,906, 5,177,079, 5,171,864,5,169,963, 5,155,122, 5,143,929, 5,143,928, 5,143,927, 5,124,455,5,124,347, 5,114,958, 5,112,846, 5,104,656, 5,098,613, 5,095,037,5,095,019, 5,086,064, 5,081,261, 5,081,147, 5,081,126, 5,075,330,5,066,668, 5,059,602, 5,043,457, 5,037,835, 5,037,811, 5,036,088,5,013,850, 5,013,751, 5,013,736, 500,654, 4,992,448, 4,992,447,4,988,733, 4,988,728, 4,981,865, 4,962,119, 4,959,378, 4,954,519,4,945,099, 4,942,236, 4,931,457, 4,927,835, 4,912,248, 4,910,192,4,904,786, 4,904,685, 4,904,674, 4,904,671, 4,897,397, 4,895,953,4,891,370, 4,870,210, 4,859,686, 4,857,644, 4,853,392, 4,851,412,4,847,303, 4,847,290, 4,845,242, 4,835,166, 4,826,990, 4,803,216,4,801,598, 4,791,129, 4,788,205, 4,778,818, 4,775,679, 4,772,703,4,767,776, 4,764,525, 4,760,051, 4,748,153, 4,725,616, 4,721,712,4,713,393, 4,708,966, 4,695,571, 4,686,235, 4,686,224, 4,680,298,4,678,802, 4,652,564, 4,644,005, 4,632,923, 4,629,793, 4,614,741,4,599,360, 4,596,828, 4,595,694, 4,595,686, 4,594,357, 4,585,755,4,579,866, 4,578,390, 4,569,942, 4,567,201, 4,563,476, 4,559,348,4,558,067, 4,556,672, 4,556,669, 4,539,326, 4,537,903, 4,536,503,4,518,608, 4,514,415, 4,512,990, 4,501,755, 4,495,197, 4,493,839,4,465,687, 4,440,779, 4,440,763, 4,435,420, 4,412,995, 4,400,534,4,355,034, 4,335,141, 4,322,420, 4,275,064, 4,244,963, 4,235,908,4,234,593, 4,226,887, 4,201,778, 4,181,720, 4,173,650, 4,173,634,4,145,444, 4,128,664, 4,125,612, 4,124,726, 4,124,707, 4,117,135,4,027,031, 4,024,284, 4,021,553, 4,021,550, 4,018,923, 4,012,527,4,011,326, 3,998,970, 3,998,954, 3,993,763, 3,991,212, 3,984,405,3,978,227, 3,978,219, 3,978,202, 3,975,543, 3,968,224, 3,959,368,3,949,082, 3,949,081, 3,947,475, 3,936,450, 3,934,018, 3,930,005,3,857,955, 3,856,962, 3,821,377, 3,821,401, 3,789,121, 3,789,123,3,726,978, 3,694,471, 3,691,214, 3,678,169, 3,624,216;

immunosuppressive agents, as disclosed in U.S. Pat. Nos. 4,450,159,4,450,159, 5,905,085, 5,883,119, 5,880,280, 5,877,184, 5,874,594,5,843,452, 5,817,672, 5,817,661, 5,817,660, 5,801,193, 5,776,974,5,763,478, 5,739,169, 5,723,466, 5,719,176, 5,696,156, 5,695,753,5,693,648, 5,693,645, 5,691,346, 5,686,469, 5,686,424, 5,679,705,5,679,640, 5,670,504, 5,665,774, 5,665,772, 5,648,376, 5,639,455,5,633,277, 5,624,930, 5,622,970, 5,605,903, 5,604,229, 5,574,041,5,565,560, 5,550,233, 5,545,734, 5,540,931, 5,532,248, 5,527,820,5,516,797, 5,514,688, 5,512,687, 5,506,233, 5,506,228, 5,494,895,5,484,788, 5,470,857, 5,464,615, 5,432,183, 5,431,896, 5,385,918,5,349,061, 5,344,925, 5,330,993, 5,308,837, 5,290,783, 5,290,772,5,284,877, 5,284,840, 5,273,979, 5,262,533, 5,260,300, 5,252,732,5,250,678, 5,247,076, 5,244,896, 5,238,689, 5,219,884, 5,208,241,5,208,228, 5,202,332, 5,192,773, 5,189,042, 5,169,851, 5,162,334,5,151,413, 5,149,701, 5,147,877, 5,143,918, 5,138,051, 5,093,338,5,091,389, 5,068,323, 5,068,247, 5,064,835, 5,061,728, 5,055,290,4,981,792, 4,810,692, 4,410,696, 4,346,096, 4,342,769, 4,317,825,4,256,766, 4,180,588, 4,000,275, 3,759,921;

analgesic agents, as disclosed in U.S. Pat. Nos. 5,292,736, 5,688,825,5,554,789, 5,455,230, 5,292,736, 5,298,522, 5,216,165, 5,438,064,5,204,365, 5,017,578, 4,906,655, 4,906,655, 4,994,450, 4,749,792,4,980,365, 4,794,110, 4,670,541, 4,737,493, 4,622,326, 4,536,512,4,719,231, 4,533,671, 4,552,866, 4,539,312, 4,569,942, 4,681,879,4,511,724, 4,556,672, 4,721,712, 4,474,806, 4,595,686, 4,440,779,4,434,175, 4,608,374, 4,395,402, 4,400,534, 4,374,139, 4,361,583,4,252,816, 4,251,530, 5,874,459, 5,688,825, 5,554,789, 5,455,230,5,438,064, 5,298,522, 5,216,165, 5,204,365, 5,030,639, 5,017,578,5,008,264, 4,994,450, 4,980,365, 4,906,655, 4,847,290, 4,844,907,4,794,110, 4,791,129, 4,774,256, 4,749,792, 4,737,493, 4,721,712,4,719,231, 4,681,879, 4,670,541, 4,667,039, 4,658,037, 4,634,708,4,623,648, 4,622,326, 4,608,374, 4,595,686, 4,594,188, 4,569,942,4,556,672, 4,552,866, 4,539,312, 4,536,512, 4,533,671, 4,511,724,4,440,779, 4,434,175, 4,400,534, 4,395,402, 4,391,827, 4,374,139,4,361,583, 4,322,420, 4,306,097, 4,252,816, 4,251,530, 4,244,955,4,232,018, 4,209,520, 4,164,514 4,147,872, 4,133,819, 4,124,713,4,117,012, 4,064,272, 4,022,836, 3,966,944;

cholinergic agents, as disclosed in U.S. Pat. Nos. 5,219,872, 5,219,873,5,073,560, 5,073,560, 5,346,911, 5,424,301, 5,073,560, 5,219,872,4,900,748, 4,786,648, 4,798,841, 4,782,071, 4,710,508, 5,482,938,5,464,842, 5,378,723, 5,346,911, 5,318,978, 5,219,873, 5,219,872,5,084,281, 5,073,560, 5,002,955, 4,988,710, 4,900,748, 4,798,841,4,786,648, 4,782,071, 4,745,123, 4,710,508;

adrenergic agents, as disclosed in U.S. Pat. Nos. 5,091,528, 5,091,528,4,835,157, 5,708,015, 5,594,027, 5,580,892, 5,576,332, 5,510,376,5,482,961, 5,334,601, 5,202,347, 5,135,926, 5,116,867, 5,091,528,5,017,618, 4,835,157, 4,829,086, 4,579,867, 4,568,679, 4,469,690,4,395,559, 4,381,309, 4,363,808, 4,343,800, 4,329,289, 4,314,943,4,311,708, 4,304,721, 4,296,117, 4,285,873, 4,281,189, 4,278,608,4,247,710, 4,145,550, 4,145,425, 4,139,535, 4,082,843, 4,011,321,4,001,421, 3,982,010, 3,940,407, 3,852,468, 3,832,470;

antihistamine agents, as disclosed in U.S. Pat. Nos. 5,874,479,5,863,938, 5,856,364, 5,770,612, 5,702,688, 5,674,912, 5,663,208,5,658,957, 5,652,274, 5,648,380, 5,646,190, 5,641,814, 3,946,022,5,633,285, 5,614,561, 5,602,183, 4,923,892, 4,782,058, 4,393,210,4,180,583, 3,965,257, 3,931,197;

steroidal agents, as disclosed in U.S. Pat. Nos. 5,863,538, 5,855,907,5,855,866, 5,780,592, 5,776,427, 5,651,987, 5,346,887, 5,256,408,5,252,319, 5,209,926, 4,996,335, 4,927,807, 4,910,192, 4,710,495,4,049,805, 4,004,005, 3,670,079, 3,608,076, 5,892,028, 5,888,995,5,883,087, 5,880,115, 5,869,475, 5,866,558, 5,861,390, 5,861,388,5,854,235, 5,837,698, 5,834,452, 5,830,886, 5,792,758, 5,792,757,5,763,361, 5,744,462, 5,741,787, 5,741,786, 5,733,899, 5,731,345,5,723,638, 5,721,226, 5,712,264, 5,712,263, 5,710,144, 5,707,984,5,705,494, 5,700,793, 5,698,720, 5,698,545, 5,696,106, 5,677,293,5,674,861, 5,661,141, 5,656,621, 5,646,136, 5,637,691, 5,616,574,5,614,514, 5,604,215, 5,604,213, 5,599,807, 5,585,482, 5,565,588,5,563,259, 5,563,131, 5,561,124, 5,556,845, 5,547,949, 5,536,714,5,527,806, 5,506,354, 5,506,221, 5,494,907, 5,491,136, 5,478,956,5,426,179, 5,422,262, 5,391,776, 5,382,661, 5,380,841, 5,380,840,5,380,839, 5,373,095, 5,371,078, 5,352,809, 5,344,827, 5,344,826,5,338,837, 5,336,686, 5,292,906, 5,292,878, 5,281,587, 5,272,140,5,244,886, 5,236,912, 5,232,915, 5,219,879, 5,218,109, 5,215,972,5,212,166, 5,206,415, 5,194,602, 5,166,201, 5,166,055, 5,126,488,5,116,829, 5,108,996, 5,099,037, 5,096,892, 5,093,502, 5,086,047,5,084,450, 5,082,835, 5,081,114, 5,053,404, 5,041,433, 5,041,432,5,034,548, 5,032,586, 5,026,882, 4,996,335, 4,975,537, 4,970,205,4,954,446, 4,950,428, 4,946,834, 4,937,237, 4,921,846, 4,920,099,4,910,226, 4,900,725, 4,892,867, 4,888,336, 4,885,280, 4,882,322,4,882,319, 4,882,315, 4,874,855, 4,868,167, 4,865,767, 4,861,875,4,861,765, 4,861,763, 4,847,014, 4,774,236, 4,753,932, 4,711,856,4,710,495, 4,701,450, 4,701,449, 4,689,410, 4,680,290, 4,670,551,4,664,850, 4,659,516, 4,647,410, 4,634,695, 4,634,693, 4,588,530,4,567,000, 4,560,557, 4,558,041, 4,552,871, 4,552,868, 4,541,956,4,519,946, 4,515,787, 4,512,986, 4,502,989, 4,495,102; the disclosuresof which are herein incorporated by reference.

Also of interest are analogs of the above compounds.

For all of the above active agents, the active agents may be present aspharmaceutically acceptable salts.

As indicated above, the active agent of the compositions are typicallypresent in a pharmaceutically acceptable vehicle or carrier, e.g., asdescribed below. In certain embodiments, the active agent is present inan amount of from about 0.1% to about 90% by weight, e.g., from about 1%to about 30% by weight of the active compound.

Pharmaceutically Acceptable Carrier

As summarized above, the compositions of the invention further include apharmaceutically acceptable vehicle (i.e., carrier). Common carriers andexcipients, such as corn starch or gelatin, lactose, dextrose, sucrose,microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate,sodium chloride, and alginic acid are of interest. Disintegratorscommonly used in the formulations of the invention includecroscarmellose, microcrystalline cellulose, corn starch, sodium starchglycolate and alginic acid.

A liquid composition may comprise a suspension or solution of thecompound or pharmaceutically acceptable salt in a suitable liquidcarrier(s), for example, ethanol, glycerine, sorbitol, non-aqueoussolvent such as polyethylene glycol, oils or water, with a suspendingagent, preservative, surfactant, wetting agent, flavoring or coloringagent. Alternatively, a liquid formulation can be prepared from areconstitutable powder. For example, a powder containing activecompound, suspending agent, sucrose and a sweetener can be reconstitutedwith water to form a suspension; and a syrup can be prepared from apowder containing active ingredient, sucrose and a sweetener.

A composition in the form of a tablet or pill can be prepared using anysuitable pharmaceutical carrier(s) routinely used for preparing solidcompositions. Examples of such carriers include magnesium stearate,starch, lactose, sucrose, microcrystalline cellulose and binders, forexample, polyvinylpyrrolidone. The tablet can also be provided with acolor film coating, or color included as part of the carrier(s). Inaddition, active compound can be formulated in a controlled releasedosage form as a tablet comprising a hydrophilic or hydrophobic matrix.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolysable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, acidity of the medium (either internal or external to thematrix) and physical and chemical properties of the active agent in thematrix.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, for example, by incorporation of activecompound and excipients into a hard gelatin capsule. Alternatively, asemi-solid matrix of active compound and high molecular weightpolyethylene glycol can be prepared and filled into a hard gelatincapsule; or a solution of active compound in polyethylene glycol or asuspension in edible oil, for example, liquid paraffin or fractionatedcoconut oil can be prepared and filled into a soft gelatin capsule.

Tablet binders that can be included are acacia, methylcellulose, sodiumcarboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropylmethyl-cellulose, sucrose, starch and ethylcellulose. Lubricants thatcan be used include magnesium stearate or other metallic stearates,stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.

Flavoring agents such as peppermint, oil of wintergreen, cherryflavoring or the like can also be used. Additionally, it may bedesirable to add a coloring agent to make the dosage form moreattractive in appearance or to help identify the product.

The compounds of the invention and their pharmaceutically acceptablesalts that are active when given parenterally can be formulated forintramuscular, intrathecal, or intravenous administration.

A typical composition for intramuscular or intrathecal administrationwill be of a suspension or solution of active ingredient in an oil, forexample, arachis oil or sesame oil. A typical composition forintravenous or intrathecal administration will be a sterile isotonicaqueous solution containing, for example, active ingredient and dextroseor sodium chloride, or a mixture of dextrose and sodium chloride. Otherexamples are lactated Ringer's injection, lactated Ringer's plusdextrose injection, Normosol-M and dextrose, Isolyte E, acylatedRinger's injection, and the like. Optionally, a co-solvent, for example,polyethylene glycol, a chelating agent, for example, ethylenediaminetetraacetic acid, and an anti-oxidant, for example, sodiummetabisulphite may be included in the formulation. Alternatively, thesolution can be freeze dried and then reconstituted with a suitablesolvent just prior to administration.

The compounds of the invention and their pharmaceutically acceptablesalts which are active on rectal administration can be formulated assuppositories. A typical suppository formulation will generally consistof active ingredient with a binding and/or lubricating agent such as agelatin or cocoa butter or other low melting vegetable or synthetic waxor fat.

The compounds of this invention and their pharmaceutically acceptablesalts which are active on topical administration can be formulated astransdermal compositions or transdermal delivery devices (“patches”).Such compositions include, for example, a backing, active compoundreservoir, a control membrane, liner and contact adhesive. Suchtransdermal patches may be used to provide continuous or discontinuousinfusion of the compounds of the present invention in controlledamounts. The construction and use of transdermal patches for thedelivery of pharmaceutical agents is well known in the art. For example,see U.S. Pat. No. 5,023,252, herein incorporated by reference in itsentirety. Such patches may be constructed for continuous, pulsatile, oron demand delivery of pharmaceutical agents.

Optionally, the pharmaceutical composition may contain otherpharmaceutically acceptable components, such a buffers, surfactants,antioxidants, viscosity modifying agents, preservatives and the like.Each of these components is well-known in the art. For example, see U.S.Pat. No. 5,985,310, the disclosure of which is herein incorporated byreference.

Other components suitable for use in the formulations of the presentinvention can be found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985).

Identifiers

Also present in the subject compositions is an identifier. Theidentifier may vary depending on the particular embodiment and intendedapplication of the composition. In certain embodiments, the identifieris a component that emits a signal upon activation by a stimulus, e.g.,by interrogation, upon contact with a target physiological location,etc. As such, the identifier may be an identifier that emits a signalwhen it contacts a target body (i.e., physiological) site. In additionor alternatively, the identifier may be an identifier that emits asignal when interrogated.

In yet other embodiments, the identifier is an inert, but identifiablemarker, e.g., an engraved identifier (such as one that is fabricatedfrom a material or materials that survive digestion). This marker maythen be identified, for example, following an autopsy or forensicexamination. It is possible to provide a more internal device within apill to determine both that its surface has partially been subject todigestion, but also that the inner pill material has also been digested.This application is particularly useful in experimental pharmacologicalsettings. The identifier of these embodiments is one that does notnecessarily emit a signal, but which can be optically inspected, e.g.,visually or machine read, to obtain information about the compositionwith which it was associated prior to administration.

While the identifier may be an identifier that does not emit a signal,in certain embodiments (as summarized above) the identifier is one thatdoes emit a signal. Depending on the needs of a particular application,the signal may be a generic signal, e.g., a signal that merelyidentifies that the composition has contacted the target site, or aunique signal, e.g., a signal which in some way uniquely identifies thata particular composition from a group or plurality of differentcompositions in a batch has contacted a target physiological site. Assuch, the identifier may be one that, when employed in a batch of unitdosages, e.g., a batch of tablets, emits a signal which cannot bedistinguished from the signal emitted by the identifier of any otherunit dosage member of the batch. In yet other embodiments, theidentifier emits a signal that uniquely identifies a given unit dosage,even from other identical unit dosages in a given batch. Accordingly, incertain embodiments the identifier emits a unique signal thatdistinguishes a given type of unit dosage from other types of unitdosages, e.g., a given medication from other types of medications. Incertain embodiments, the identifier emits a unique signal thatdistinguishes a given unit dosage from other unit dosages of a definedpopulation of unit dosages, e.g., a prescription, a batch or a lifetimeproduction run of dosage formulations. In certain embodiments, theidentifier emits a signal that is unique, i.e., distinguishable, from asignal emitted by any other dosage formulation ever produced, where sucha signal may be viewed as a universally unique signal (e.g., analogousto a human fingerprint which is distinct from any other fingerprint ofany other individual and therefore uniquely identifies an individual ona universal level). In one embodiment, the signal may either directlyconvey information about the composition, or provide an identifyingcode, which may be used to retrieve information about the compositionfrom a database, i.e., a database linking identifying codes withcompositions.

The identifier may be any component or device that is capable ofgenerating a detectable signal following activation in response to astimulus. In certain embodiments, the stimulus activates the identifierto emit a signal once the composition comes into contact with aphysiological target site, e.g., as summarized above. For example, apatient may ingest a pill that upon contact with the stomach fluids,generates a detectable signal. Depending on the embodiment, the targetphysiological site or location may vary, where representative targetphysiological sites of interest include, but are not limited to: alocation in the gastrointestinal tract (such as the mouth, esophagus,stomach, small intestine, large intestine, etc.); another locationinside the body, such as a parental location, vascular location, etc.;or a topical location; etc.

In certain embodiments the stimulus that activates the identifier is aninterrogation signal, such as a scan or other type of interrogation. Inthese embodiments, the stimulus activates the identifier, therebyemitting a signal which is then received and processed, e.g., toidentify the composition in some manner. In certain of theseembodiments, the identifier may include a power source that transducesbroadcast power and a signal generating element that modulates theamount of transduced power, such that a signal is not emitted from theidentifier but instead the amount of broadcast power transduced by theidentifier is detected and employed as the “signal.” Such embodimentsare useful in a variety of applications, such as applications where thehistory of a given composition is of interest, e.g., as reviewed ingreater detail below.

In certain embodiments, the identifier is dimensioned to be complexedwith the active agent/pharmaceutically acceptable carrier component ofthe composition so as to produce a composition that can be readilyadministered to a subject in need thereof. As such, in certainembodiments, the identifier element is dimensioned to have a widthranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm toabout 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such asfrom about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mmto about 1 mm, such as from about 0.05 mm to about 0.3 mm, includingfrom about 0.1 mm to about 0.2 mm. In certain embodiments the identifieris 1 mm3 or smaller, such as 0.1 mm³ or smaller, including 0.2 mm³ orsmaller. The identifier element may take a variety of differentconfigurations, such as but not limited to: a chip configuration, acylinder configuration, a spherical configuration, a disc configuration,etc., where a particular configuration may be selected based on intendedapplication, method of manufacture, etc.

The identifier may generate a variety of different types of signals,including but not limited, RF, magnetic, conductive (near field),acoustic, etc.

As is known in the art (see, e.g., J. D. Jackson, ClassicalElectrodynamics, 2nd Edition, pp. 394-396 (1975)), the electric (E) andmagnetic (B) fields for radiation of an oscillating electric dipoleantenna with an angular frequency ω and corresponding wave number k(where k=ω/c, with c being the speed of light in the relevant medium)are given by the equations:

$\begin{matrix}{{B = {{k^{2}\left( {n \times p} \right)}\frac{e^{ikr}}{r}\left( {1 - \frac{1}{ikr}} \right)}};{and}} & (1) \\{{E = {{{k^{2}\left( {n \times p} \right)} \times n\frac{e^{ikr}}{r}} + {\left\lbrack {{3{n\left( {n \cdot p} \right)}} - p} \right\rbrack\left( {\frac{1}{r^{3}} - \frac{ik}{r^{2}}} \right)e^{ikr}}}},} & (2)\end{matrix}$

where n is a unit vector in the direction from the center of the dipolesource to a location x at a distance r from the source, and p is aspace-integrated density of electric charge given by (p=∫x′ρ(x′)d³x′)

As can be seen from Eqs. (1) and (2), in the “far field” region, wherer>>λ (where the wavelength λ=2π/k), the electric and magnetic fields aredominated by terms that decrease with distance as 1/r. In this region,mutually perpendicular electric and magnetic fields feed off one anotherto propagate the signal through space. Where λ˜r, the 1/r² (“induction”)terms in Eqs. (1) and (2) become significant, and where λ>>r, anadditional quasi-electrostatic term that varies as 1/r³ also becomessignificant.

Conventional RF communication takes place at distances r˜λ to r>>λ. Forinstance, implantable medical devices such as pacemakers typicallycommunicate in the 405-MHz frequency band, corresponding to wavelengthsof 0.75 meters, somewhat smaller than the scale of a human body. As isknown in the art, higher frequencies are advantageously not used becausestructures within the body begin to absorb radiation, leading toundesirable signal loss; substantially lower frequencies (longerwavelengths) are generally regarded as undesirable because much of theenergy is redirected into the induction and/or quasi-static fieldcomponents rather than the far-field component that can be sensed usingconventional antennas. It should also be noted that RFID applicationswith a transponder and a base unit typically use wavelengths such thatr˜λ and generally rely on magnetic induction to transmit power from thetransponder to the base unit. In certain embodiments, these RF signalsare employed.

In contrast to these approaches, certain embodiments of the presentinvention advantageously operate at wavelengths much larger than thehuman body (λ>>1 meter) to communicate information within the patient'sbody, e.g., as described in U.S. Provisional Application Ser. No.60/713,680; the disclosure of which is herein incorporated by reference.For instance, in some embodiments, frequencies on the order of 100 kHz,corresponding to wavelengths of around 3 km (in air), are advantageouslyused. At distances r that are short as compared to the wavelength λ, thequasi-static electric field term in Eqs. (1) and (2) dominates, and thusthe propagating signal is predominantly electrical rather thanelectromagnetic. Such signals readily propagate in a conductive mediumsuch as the human body. For instance, at a frequency of 100 kHz anddistances on the order of 1-2 meters, the quasi-static (1/r³) componentof Eq. (2) is estimated to be on the order of 10⁶ times stronger thanthe far-field (1/r) component. Thus, long-wavelength signaling usingnear-field coupling is efficient. Further, because the signals arerequired to travel relatively short distances (typically 2 meters orless), detectable signals can be transmitted using very small antennas.

A wide range of frequencies may be used for transmission of signals. Insome embodiments, the transmission frequency is within the “LF” band(low frequency, defined as 30-300 kHz) of the RF spectrum, below thefrequency range of AM radio (around 500 to 1700 kHz). Within the LFband, the range from 160-190 kHz has been designated by the FCC forexperimental use, with specified upper limits on external signalstrength. In embodiments of the present invention where the signals arelargely confined within the patient's body as described below, thisexperimental band can be used.

However, the invention is not limited to the 160-190 kHz band or to theLF (30-300 kHz band). Lower bands may also be used; for instance, in theVLF band (3-30 kHz, wavelengths of 10-100 km in air), signals canpenetrate water to a distance of 10-40 meters. Since the electricalproperties of the human body are similar to those of salt water, it isexpected that signals in this band would also readily propagate throughthe body. Thus, any frequency band corresponding to a wavelength that isat least an order of magnitude larger than the human body—e.g., λ˜10 mor longer, or frequencies on the order of 30 MHz or below—can be used.

While there is no necessary lower limit on the frequency of signalsused, several practical considerations may affect the choice offrequency. For instance, it is well known that the human body carrieslow-level oscillating signals induced by nearby AC-powered devices,which operate at 60 Hz (US) or similar frequencies in other parts of theworld. To avoid interference caused by AC electrical power systems,frequencies near 60 Hz are advantageously not used. In addition, as isknown in the art, longer wavelengths correlate with lower informationtransfer rates, and the information-transfer capacity at longwavelengths (e.g., below the 3 kHz-30 kHz VLF band) may be too small forthe amount of information that is to be transferred in a particularsystem. Further, longer wavelengths generally require longer dipoleantennas to produce a detectable signal, and at some point the antennasize may become a limiting factor in frequency selection.

According to some embodiments of the invention, given a suitable choiceof frequency, a signal strong enough to travel to a receiver within thebody can be generated using a very small antenna. For instance, 100 kHzsignals generated by a dipole antenna just a few millimeters long can bepropagated to a receiver antenna placed 1-2 meters away. Thisquasi-electrostatic transmission is believed to be aided by the factthat the implanted antenna is directly in contact with a conductivemedium, for example, the patient's tissues. For purposes of analyzingelectrical properties, human tissue can be approximated as anelectrolyte solution with electrical properties comparable to those ofsalt water. Thus, as in an electrolyte bath, the quasi-electrostaticfield created by an oscillating dipole antenna induces an oscillatingcurrent in the body. As a result of the inherent electrical resistivityof the body (comparable to salt water), the oscillating current createsoscillating potential variations within the body that can be sensedusing a suitable receiver. (See, e.g., L. D. Landau et al.Electro-dynamics of Continuous Media, Ch. 3 (1960)). Examples ofsuitable receivers include the leads of a pacemaker, which create adipole with an axis of about 20 cm or any other implanted wires withlength from 10-100 cm.

It should be noted that these currents are undesirable in the context ofconventional RF communication, in which current flow in the near fieldleads to power loss in the far-field. In fact, many RF transmittersinclude devices designed to minimize near-field current leakage. Innear-field transmitters of these embodiments of the present invention,maximizing such currents is desirable.

Further, for quasi-electrostatic signals, the patient's skinadvantageously acts as a conductive barrier, confining the signalswithin the patient's body. This confines the signals within the body andalso makes it difficult for stray external signals to penetrate the bodyand create noise or interference in the transmitted signals. Confinementof the signals can mitigate, to some extent, the 1/r³ falloff of thenear-field signal, further reducing power requirements. Such effectshave been observed in the laboratory, e.g., in a salt water bath, inwhich the water/air interface acting as a conductive barrier. Similareffects have been observed in communicating with submarines via RFtransmission in the ELF (3-30 Hz) and SLF (30-300 Hz) bands. Theseeffects have also been observed in sonar communications;

although sonar uses acoustic, rather than electrical or electromagnetic,fields to transmit information, the surface of the water acts as aconductive barrier for acoustic energy and mitigates the fall-off ofsignal intensity with distance.

As a result of these phenomena, a transmitter with a very small antennaand a small power source are sufficient to create a near-field signalthat is detectable within the patient's body. For instance, the antennacan be formed by a pair of electrodes a few millimeters or less inlength, spaced apart by a few millimeters, with oscillating voltages ofopposite phase applied to create an oscillating electric dipole. Suchantennas can be disposed almost anywhere within the body.

Further, in some embodiments, the frequency, transmitter antenna length,and receiver antenna length are selected such that only microwatts ofpower are required to produce a detectable signal, where conventional RFcommunication (e.g., at around 405 MHz) would require at leastmilliwatts. Accordingly, very compact power supplies that produce onlysmall amounts of power can be used; examples are described in Section IVbelow.

As such, depending on the particular embodiment of interest, thefrequency may range from about 0.1 Hz or lower to about 100 mHz orhigher, e.g., from about 1 kHz to about 70 mHz, including from about 5kHz to about 200 kHz.

In certain embodiment, the signal that is emitted by the identifier isan acoustic signal. In these embodiments, any convenient acoustic signalgeneration element may be present in the identifier, e.g., apiezoelectric element, etc.

The transmission time of the identifier may vary, where in certainembodiments the transmission time may range from about 0.1 μsec to about4 hours or longer, such as from about 1 sec to about 4 hours. Dependingon the given embodiment, the identifier may transmit a signal once ortransmit a signal two or more times, such that the signal may be viewedas a redundant signal.

In certain embodiments, the identifier may be one that is programmablefollowing manufacture, in the sense that the signal generated by theidentifier may be determined after the identifier is produced, where theidentifier may be field programmable, mass programmable, fuseprogrammable, and even reprogrammable. Such embodiments are of interestwhere uncoded identifiers are first produced and following incorporationinto a composition are then coded to emit an identifying signal for thatcomposition. Any convenient programming technology may be employed. Incertain embodiments, the programming technology employed is RFIDtechnology. RFID smart tag technology of interest that may be employedin the subject identifiers includes, but is not limited to: thatdescribed in U.S. Pat. Nos. 7,035,877; 7,035,818; 7,032,822; 7,031,946,as well as published application no. 20050131281, and the like, thedisclosures of which are herein incorporated by reference. With RFID orother smart tag technology, a manufacturer/vendor may associate a uniqueID code with a given identifier, even after the identifier has beenincorporated into the composition. In certain embodiments, eachindividual or entity involved in the handling of the composition priorto use may introduce information into the identifier, e.g., in the formof programming with respect to the signal emitted by the identifier,e.g., as described in U.S. Pat. No. 7,031,946 the disclosure of which isherein incorporated by reference.

The identifier of certain embodiments includes a memory element, wherethe memory element may vary with respect to its capacity. In certainembodiments, the memory element has a capacity ranging from about 1 bitto 1 gigabyte or more, such as 1 bit to 1 megabyte, including from about1 bit to about 128 bit. The particular capacity employed may varydepending on the application, e.g., whether the signal is a genericsignal or coded signal, and where the signal may or may not be annotatedwith some additional information, e.g., name of active agent, etc.

Identifier components of embodiments of the invention have: (a) anactivation component and (b) a signal generation component, where thesignal generation component is activated by the activation component toproduce an identifying signal, e.g., as described above.

Activation Component

The activation component is a component that activates the signalgeneration element to emit a signal upon experience of a stimulus, e.g.,contact of the composition with a target physiological site of interest,such as the stomach. The activation component may be configured to beactivated in a number of different ways. The following sections detailcertain different ways in which the identifier may be activated. As canbe seen from the following review, the activation component may or maynot be integrated with a power source, e.g., a battery. Illustrativeactivation approaches include, but are not limited to: BatteryCompletion, e.g., Battery activated by electrolyte addition and Batteryactivated by cathode or anode addition; Battery connection, e.g.,Battery activated by conductor addition; Transistor-mediated BatteryConnection, e.g., Battery activated by transistor gate, GeometryModification, Detection of Geometry Modification by Resonant Structure,Pressure Detection, Resonant Structure Modification; etc. Each of theseillustrative activation approaches is now reviewed in greater detail.

Battery Completion Battery Activated by Electrolyte Addition

In these embodiments, the battery includes, when completed, a cathode,an anode, and an electrolyte. When the composition (e.g., pill) isadministered, e.g., ingested, and travels through the esophagus, itproceeds to enter the stomach. The cathode and anode provided within thecomposition do not constitute a full battery. However, as thecomposition dissolves to expose the cathode and anode, the stomach fluidacts as the electrolyte component of the battery. The added component ofthe stomach fluid thus completes the battery. Therefore, as thecomposition contacts the target site, e.g., by entering the stomach anddissolving to the point of cathode and anode exposure, a power source isprovided which activates the identifier, e.g., in chip configuration.The data signal is then transmitted. This configuration is described ingreater detail below, e.g., in terms FIG. 4.

Battery Activated by Cathode or Anode Addition

In an extension of this approach, the system is activated by having thetriggering event add a cathode or anode component, with the electrolytebeing intrinsic in the partial, pre-battery configuration. The batteryis completed, producing power and activating the composition, althoughnot necessarily at the identical point of time.

Battery Connection Battery Activated by Conductor Addition

In another embodiment of the present invention, the battery is connectedto the circuitry when it enters the stomach. The battery becomesconnected, and thus activates the identifier, by conductor addition. Inthis case, there is a physically complete battery and a complete chip.When these two components are awash in physiological fluid, such as inthe stomach, they become electronically connected. This triggering eventelectrically connects the battery to the signaling microchip, thusactivating the smart pill.

Transistor-Mediated Battery Connection Battery Activated by TransistorGate

Another design allowing the battery and the chip together to activatethe smart pill has the feature of a transistor gate between the batteryand the reporting chip. Once the transistor gate is switched on, such asby activation with the stomach, the reporting signal is transmitted.

There are numerous methods well known to the ordinary skilled artisanfor turning on a transistor gate. Most of them involve activating thegate by closing a switch, which can include a transistor switch or othertypes of switches.

The gate can be activated by applying a small gate current. This is how,for example, transistors are typically activated. The gate current canbe generated in any number of ways well known to the ordinary skilledartisan. Any circuitry which detects the presence of the pill in theenvironment of interest, such as the stomach, generates the gate currentand turns the system on.

The gate current can be turned on by detecting a conductivity variation.For instance, a circuit can be provided that detects a small change inthe conductivity of the stomach. While the stomach is conductive, thepill might not be. As a result, when the conductivity variation isdetected, the transistor gate is activated, turning the smart pill onand generating a reporting signal.

The conductivity can be modulated by a change in the solutionconcentration. By example, the system detects a different solutionconcentration in the stomach in contrast to areas outside the stomach.The solution pH is detected, by a modulation of the conductivity, whichturns on the gate, and turn on the pill generating a reporting signal.

The stomach contains ionic conductive fluids. Those ionic conductivefluids can be employed to modulate the conductivity of the gate and turnon the smart pill, generating a reporting signal. Individual enzymes canbe detected in the stomach. For instance, a chem-FET can be employedthat looks for the pepsin content in the stomach, turning the pill on,thus reporting the presence of the enzyme.

Temperature change can also be detected using the innovations of thepresent invention. The stomach is typically a steady 37° C. Areasoutside the stomach are more typically 20° C. or less. When the pillenters the stomach and becomes heated up, the pill is so designed thatthis adjusts the conductivity and turn the identifier on, generating areporting signal.

The conductivity of the transistor can be modified by a microscopicproperty called carrier mobility. A detection approach using thisproperty uses the transistor itself as a detector. The carrier mobilityis modulated by temperature, a well-known phenomenon. In this manner,the transistor is used as a temperature sensor by using that transistorto turn on the smart pill, generating a reporting signal.

Another approach is to change the charge on the gate of a MOSFETtransistor. The gate charge can be modulated by the factors to bedetected. This is again a configuration using the transistor to turn onthe circuit, generating a reporting signal.

In another configuration, the gate charge is modulated by a material tobe detected in the solution. A specific ion would preferentially changethe gate charge. This system is modulated by a crystal potential. Acrystal potential occurs when crystals generate electric fields undercertain circumstances.

The electric field can change the charge on the gate, turning on thetransistor and generating a reporting signal. This change may bemodulated by a chemical potential, resulting from an osmotic or ionicprocess. This causes charge to accumulate on the gate, thereby, turningit on and generating a reporting signal.

A change in the electrical potential can also cause a reporting signalusing a variety of potentials. For example, a gravitational potentialcan detect the change in height of the detector. In the case of apatient swallowing the pill, the change in pill height would indicateingestion.

In another embodiment, a transistor gate has associated with it acapacitance. That capacitance is then modulated by certain propertiespeculiar to the target site, e.g., the stomach.

In one case, the capacitance is changed by being enveloped in thestomach. This effect on the capacitance is then detected. The gatecharge is modulated by change in the carrier concentration. The carrierconcentration is modulated by temperature. This approach provides aslightly different approach, but similar in concept to using thetransistor as a temperature sensor as above.

Geometry Modification

A transistor structure is also provided that has a geometry thatchanges. Gate capacitance is determined by a change in geometry whichoccurs in the stomach, detecting a change in capacitance. These changescan take place in a variety of ways, for example, as further describedbelow.

A variety of physiologic factors change the geometry. Pressure in thestomach different than pressure outside occurs with the naturalsqueezing during the production of chyme, as well as at other times.This changes the gate capacitance. The change is detected by having adielectric on the gate. In this case, the gate consists of a number oflayers, one of which is the dielectric.

In an additional embodiment, the enzymes of the stomach dissolve thedielectric, changing the gate capacitance, which is then detected.Various physical and chemical conditions within the stomach dissolvethat gate dielectric, thereby activating the circuit.

Detection of Geometry Modification by Resonant Structure

A resonant structure on the gate is provided in other variants. In thiscase, a mechanical structure is provided that has a characteristicfrequency. This frequency is excited by the triggering event, andmeasured. Various interactions with the stomach will cause a change inthat resonance.

Pressure Detection

Gate capacitance and resonance with modulation source can also beutilized for detection. In this case, an excitation is provided to theresonance structure from a modulation source, such as a sound wave. Thegate capacitance of that resonance structure can be used to detectingpressure waves. A resonance structure sits out in the stomach and ishooked up to a detection circuit on a transistor. In the stomach, theresonance circuit detects pressure waves.

Of pressure sound waves within the body, there are particular soundsthat are characteristic, such as the heart beat and respiration. Thesesounds are detected and used to turn the circuit on.

Pressure waves are also detected by resonant Q factor modulation. Qfactor modulation can be accomplished in a number of different manners.The resonance structure has two components, a frequency and a Q factor.The Q factor is modulated by detecting some environmental change.

Resonant Structure Modification

By example, the structure has a very different Q factor in air than itdoes in the fluid of the stomach. Thus, the dampening can be detected bythe fluid viscosity. Additionally, the structure can be configured to beeaten away by the acid or some of the enzymes in the stomach, whichchanges the cue.

Degradation by stomach acid or enzymes also changes the resonantfrequency. It is simple to detect the frequency shift of such astructure. The frequency is shifted as this structure is changed in thestomach. There are two approaches to modifying the structure. Acatabolic process can occur where the structure gets dissolved, which iseasily detectable. Also, an anabolic process would occur where an enzymefrom the stomach binds to this structure, making it larger. This effectwill also modify the resonance structure. The resonance modification isdetected either as a frequency change or a Q factor modulation.

Battery Power Sources

As reviewed above, in certain embodiments, the activation element is apower source that is turned on upon contact of the power source with atarget site, e.g., a physiological target site, such as the stomach,e.g., stomach acid. In certain embodiments, the power source is abattery that is turned on to provide power upon contact with thephysiological target site, where the battery is coupled to the signalgeneration component such that when the battery is turned on, the signalgeneration component emits the identifying signal.

In certain embodiments, the battery that is employed is one thatcomprises two dissimilar materials which constitute the two electrodesof the battery. In certain embodiments, these two materials are shieldedfrom the surrounding environment by an additional layer of material.When the shielding material (e.g., active agent/carrier matrix), isdissolved or eroded by the surrounding fluid, the electrode materialsare exposed and come in contact with the body fluid, such as stomachacid or other types of electrolyte fluid. A potential difference, thatis, a voltage, is generated between the electrodes as a result of therespective oxidation and reduction reactions incurred to the twoelectrode materials. A voltaic cell, or battery, can be thereby formed.Accordingly, in embodiments of the invention, such batteries areconfigured such that when the two dissimilar materials are exposed tothe target site, e.g., the stomach, the digestive tract, etc., duringthe physical and chemical erosion of the composition in which the signalgeneration element is present, a voltage is generated. In suchembodiments, the power source described above is not a “battery” in thecommon sense of the word, but rather as defined in the discipline ofphysics. The two dissimilar materials in an electrolyte are at differentpotentials, similar to the physics model of a ‘potato battery’. As anexample, copper and zinc when put into a cell have different potentials.Similarly, gold and magnesium have different potentials. As a result, apotential difference between the two dissimilar materials is generated.

Various battery-activation configurations are possible. Representativetypes of cell-activation approaches include, but are not limited to:activation by presence of electrolyte, activation by presence of acathode material, activation by presence of a conductive material.

After the battery is activated, further activation configurations can beemployed to activate the signal generation component. For example, thesignal generation component can be activated through the activation ofthe gate of a metal oxide semiconductor (MOS) circuit, such as a CMOSswitch. Activation of the gate of the MOS circuit can be based on one ormore parameters, which include but are not limited to: gate current,gate charge, and gate capacitance.

The gate current, for activation purposes, can be a function of theconductivity of surrounding body fluids or tissues. Such conductivitycan further be a function of one or more parameters, which include butare not limited to: solution concentration, solution pH value, ioniccontent of solution, enzymatic content of solution, temperature, andcarrier mobility. Carrier mobility can also be a function oftemperature.

Similarly, the gate charge can be a function of one or more parameters,which include but are not limited to: solution composition, crystalpotential, electrical potential, gravitational potential, gatecapacitance, and carrier concentration. The carrier concentration canalso be a function of temperature.

The gate capacitance can be a function of the capacitive geometry of thegate, which can further be a function of pressure, a resonant input, orthe characteristics of a dielectric material coupled to the gate. Thecharacteristics of the dielectric material can vary with one or moreparameters, which include but are not limited to: chemical contents of adigestive tract, chemical character of a physiological location, andamount of dissolution of the dielectric material in body fluids.

In certain embodiments, the battery is one that is made up of activeelectrode materials, electrolyte, and inactive materials, such ascurrent collectors, packaging, etc. The active materials are any pair ofmaterials with different electrochemical potentials. Suitable materialsare not restricted to metals, and in certain embodiments the pairedmaterials are chosen from metals and non-metals, e.g., a pair made up ofa metal (such as Mg) and a salt (such as Cup. With respect to the activeelectrode materials, any pairing of substances—metals, salts, orintercalation compounds—with suitably different electrochemicalpotentials (voltage) and low interfacial resistance are suitable.

A variety of different materials may be employed as the batteryelectrodes. In certain embodiments, electrode materials are chosen toprovide for a voltage upon contact with the target physiological site,e.g., the stomach, sufficient to drive the signal generation element ofthe identifier. In certain embodiments, the voltage provided by theelectrode materials upon contact of the metals of the power source withthe target physiological site is 0.001 V or higher, including 0.01 V orhigher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5volts or higher, and including 1.0 volts or higher, where in certainembodiments, the voltage ranges from about 0.001 to about 10 volts, suchas from about 0.01 to about 10 V.

Materials and pairings of interest include, but are not limited to thosereported in Table 1 below.

TABLE 1 Anode Cathode Metals Magnesium, Zinc Sodium (†), Lithium (†)Iron Salts Copper salts: iodide, chloride, bromide, sulfate, formate,(other anions possible) Fe³⁺ salts: e.g. orthophosphate, pyrophosphate,(other anions possible) Oxygen (††) on platinum, gold or other catalyticsurfaces Intercalation Graphite with Li, K, Ca, Na, Vanadium oxidecompounds Mg Manganese oxide †Protected anodes: certain high energyanode material such as Li, Na, and other alkali metals are unstable intheir pure form in the presence of water or oxygen. These may however beused in an aqueous environment if stabilized. One example of thisstabilization is the so-called “protected lithium anode” developed byPolyplus Corporation (Berkeley, CA), where a polymer film is depositedon the surface of lithium metal to protect it from rapid oxidation andallow its use in aqueous environment or air ambient. (Polyplus has IPpending on this). ††Dissolved oxygen can also serve as a cathode. Inthis case, the dissolved oxygen in the bodily fluids would be reduced toOH— at a suitable catalytic surface such at Pt or gold. Other catalystsare also possible.

In certain embodiments, one or both of the metals may be doped with anon-metal, e.g., to enhance the voltage output of the battery.Non-metals that may be used as doping agents in certain embodimentsinclude, but are not limited to: sulfur, iodine and the like.

In certain embodiments, the electrode materials are copper iodine (CuI)as the anode and magnesium (Mg) as the cathode. Embodiments of thepresent invention use electrode materials that are not harmful to thehuman body.

In certain embodiments, the batteries have a small form factor.Batteries may be 10 mm³ or smaller, such as 1.0 mm³ or smaller,including 0.1 mm³ or smaller, including 0.02 mm³ or smaller. As such, incertain embodiments, the battery element is dimensioned to have a widthranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm toabout 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such asfrom about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mmto about 1 mm, such as from about 0.05 mm to about 0.3 mm, includingfrom about 0.1 mm to about 0.2 mm.

As reviewed below, in certain embodiments the battery has a split orsegmented configuration.

In certain embodiments, the battery is one which is free of packaging.As such, the electrodes are exposed and not protected by any protectingor sealing structure. As such, following removal of the activeagent/carrier matrix material with which the battery may be associated,the battery per se does not itself include an protective packaging suchthat the electrodes are free to contact the electrolyte at the targetphysiological location.

In certain of these embodiments, the battery power source may be viewedas a power source that exploits reverse electrolysis in an ionicsolution such as gastric fluid, blood, or other bodily fluids and sometissues. FIG. 4 illustrates an identifier 30 having a signal generationelement 40 powered by reverse electrolysis. Signal generation element 40is electrically connected to metal electrodes 32 and 33, which are madeof two different materials and are electrically insulated from eachother. When metal electrodes 32 and 33 are immersed in an ionic solution39, a potential difference develops between them; for instance,electrode 33 rises to a higher potential V+ while electrode 32 falls toa lower potential V−. This potential difference can be used to powercircuitry 40.

Electrodes 32 and 33 can be implemented in various ways; for instance,areas on opposing surfaces of an integrated circuit chip can be coatedwith two different metals, and the entire chip can be placed in theionic solution. Alternatively, electrodes 32 and 33 may extend away fromelement 40 as shown. Other arrangements may also be used.

As illustrated above, electrodes 32 and 33 can be made of any twomaterials appropriate to the environment in which the identifier 30 willbe operating. For instance, in some embodiments where ionic solution 39comprises stomach acids, electrodes 32 and 33 may be made of a noblemetal (e.g., gold, silver, platinum, palladium or the like) so that theydo not corrode prematurely. Alternatively, the electrodes can befabricated of aluminum or any other conductive material whose survivaltime in the applicable ionic solution is long enough to allow identifier30 to perform its intended function.

Where the power source is a battery, the battery may be fabricated in anumber of different ways. In certain embodiments, fabrication protocolswhich may be categorized as “planar” processing protocols are employed,as developed in greater detail below.

Additional Power Sources

Other sources, internal or external to the remote device, may also beemployed in addition to or instead of those described above. Forexample, chemical or radioisotope batteries with a suitable form factormay be used to power some remote devices. Recently-developed fuel cellsthat use blood as an energy source can be miniaturized and used toprovide electrical energy for a low-power microchip. Piezoelectriccrystals that convert mechanical energy (e.g., compression) toelectrical energy can be employed for remote devices disposed wheresuitable mechanical forces can be brought to bear, such as in or aroundthe heart, stomach, joints, or other moving parts of the body. In yetother embodiments, a power source modeled on the cellular energyfactory, with power being extracted from ATP in the blood so that blood,in effect, “nourishes” the identifier, is employed. In otherembodiments, acoustic energy (e.g., ultrasound) can be coupled into aremote device through piezoelectric or similar converters.

In yet other embodiments, the activation element is not an on boardpower source, but an element that is powered from a separate powersource and provides an activation signal to the signal generationcomponent upon contact of the composition with the target site. Forexample, the activation element may be coupled to a power receiver whichis configured to receive broadcast power and transduce the broadcastpower into a form suitable for driving the signal generation element. Incertain embodiments, the power receiver may be a coil. Alternatively,the activator component may be powered by a distinct power source, e.g.,a sealed battery, a power element that converts mechanical energy of thepill into electrical power, e.g., a piezoelectric power element, etc. Assuch, the activator may or may not itself be the power source, and inthose embodiments where it is not the power source, the identifier mayinclude a distinct power source, such as receiver or power generator.

Signal Generation Component

The signal generation component of the identifier element is a structurethat, upon activation by the activation component, emits a detectablesignal, e.g., that can be received by a receiver, e.g., as described ingreater detail below. The signal generation component of certainembodiments can be any convenient device that is capable of producing adetectable signal and/or modulating transduced broadcast power, uponactivation by the activation component. Detectable signals of interestinclude, but are not limited to: conductive signals, acoustic signals,etc. As reviewed above, the signals emitted by the signal generator maybe generic or unique signals, where representative types of signals ofinterest include, but are not limited to: frequency shift coded signals;amplitude modulation signals; frequency modulation signals; etc.

In certain embodiments, the signal generation element includescircuitry, as developed in more detail below, which produces orgenerates the signal. The type of circuitry chosen may depend, at leastin part, on the driving power that is supplied by the power source ofthe identifier. For example, where the driving power is 1.2 volts orabove, standard CMOS circuitry may be employed. In other embodimentswhere the driving power ranges from about 0.7 to about 1.2 V,sub-threshold circuit designs may be employed. For driving powers ofabout 0.7 V or less, zero-threshold transistor designs may be employed.

In certain embodiments, the signal generation component includes avoltage-controlled oscillator (VCO) that can generate a digital clocksignal in response to activation by the activation component. The VCOcan be controlled by a digital circuit, which is assigned an address andwhich can control the VCO with a control voltage. This digital controlcircuit can be embedded onto a chip that includes the activationcomponent and oscillator. Using amplitude modulation or phase shiftkeying to encode the address, an identifying signal is transmitted.

The signal generation component may include a distinct transmittercomponent that serves to transmit the generated signal to a remotereceiver, which may be internal or external to the patient, as reviewedin greater detail below. The transmitter component, when present, maytake a number of different configurations, e.g., depending on the typeof signal that is generated and is to be emitted. In certainembodiments, the transmitter component is made up of one or moreelectrodes. In certain embodiments, the transmitter component is made upof one or more wires, e.g., in the form of antenna(e). In certainembodiments, the transmitter component is made up of one or more coils.As such, the signal transmitter may include a variety of differenttransmitters, e.g., electrodes, antennas (e.g., in the form of wires)coils, etc. In certain embodiments, the signal is transmitted either byone or two electrodes or by one or two wires. A two-electrodetransmitter is a dipole; a one electrode transmitter forms a monopole.In certain embodiments, the transmitter only requires one diode drop ofpower.

In some embodiments, the transmitter unit uses an electric dipole orelectric monopole antenna to transmit signals. FIG. 6A illustrates adipole antenna. Oscillator 504 provides driving signals (ϕ and aninverted signal denoted herein as /ϕ) to an electrode driver 506. FIG.6C is a circuit diagram showing details of a dipole electrode driver 600implemented using conventional CMOS driver circuits. Electrode 602 isdriven to a potential E₀ by transistors 604, 606 in response to drivingsignal ϕ while electrode 608 is driven to a potential E₁ by transistors610, 612 in response to inverted driving signal /ϕ. Since drivingsignals ϕ and ϕ oscillate with opposite phase, potentials E₀ and E₁ alsooscillate with opposite phase. It will be appreciated that driver 600and all other electronic circuits described herein can be implementedusing sub-micron CMOS processing technologies known in the art; thus,the size of the circuitry is not a limiting factor on the size of aremote device.

In some embodiments, a monopole antenna can be substituted for thedipole antenna of FIG. 6A. FIG. 6D illustrates a driver circuit for amonopole antenna that can be implemented in conventional CMOS integratedcircuits. This antenna driver is generally similar to one half of thedriver circuit of FIG. 6C, with driver transistors 702, 704 driving asingle electrode 706 to a potential E_(m) in response to driving signal4).

In either the dipole or monopole case, the driver circuit is powered bya potential difference (ΔV) between terminals V+ and V−. This potentialdifference, which can be constant or variable, as desired.

FIG. 6A is a block diagram of a transmitter signal generation element500 for an identifier according to an embodiment of the presentinvention. In this embodiment, generation element 500 receives a signalM from the activation component which activates the signal generationelement to produce and emit a signal. Signal generation element 500includes control logic 502, an oscillator 504, an electrode driver 506,and an antenna 508 (in this instance, a pair of electrodes operated asan electric dipole antenna). In operation, oscillator 504 generates anoscillating signal (waveform) in response to signals from control logic502. The signals from control logic 502 can start or stop the oscillatorand in some embodiments can also shape one or more aspects of theoscillatory signal such as amplitude, frequency, and/or phase.Oscillator 504 provides the waveform to electrode driver 506, whichdrives current or voltage on antenna 508 to transmit a signal into theconductive medium of body tissues or fluids.

Depending on a given embodiment, the signal may or may not be modulated.For example, in certain embodiments the frequency of the signal may beheld constant. In yet other embodiments, the signal may be modulated insome manner, e.g., via carrier based modulate schemes, ultra-wide band(or time domain based) modulation schemes, etc.

Referring again to FIG. 6A, in some embodiments, oscillator 504 operatesat a constant frequency. The receipt of a constant-frequency signal inand of itself can provide useful information, e.g., that a remote deviceis present and operational. In some embodiments, oscillator 504modulates its signal to encode additional information.

Information can be encoded in various ways, generally by modulating(varying) some property of the transmitted signal, such as frequency,amplitude, phase, or any combination thereof. Modulation techniquesknown in the art may be employed.

In general, information can be transmitted using analog or digitaltechniques. “Analog techniques” refers generally to instances in whichthe modulated property is varied in different degrees, with the degreeof variation being correlated to a value representing the information tobe transmitted. For instance, suppose that element 500 is transmitting asignal. Oscillator 504 can be designed to operate over some range offrequencies. “Digital techniques” refers generally to instances in whichthe information to be transmitted is represented as a sequence of binarydigits (bits), and the signal is modulated based on the bit stream. Forinstance, suppose again that transmitter 500 is transmitting a signalusing digital techniques. Oscillator 504 can be designed to operate atleast two different frequencies, with one frequency corresponding to bitvalue 0 and another frequency corresponding to bit value 1. Inembodiments of the present invention, either analog techniques, digitaltechniques, or a combination thereof can be used to transmitinformation. In addition, various types of modulation may beimplemented.

For instance, in one embodiment, frequency modulation is used.Oscillator 504 can be a voltage-controlled oscillator (VCO), anoscillator circuit in which the oscillation frequency depends on anapplied voltage. Control logic 502 supplies an appropriate voltage(e.g., reflecting the value of the measurement data, M), and thefrequency of the signal indicates the value of the data. In anotherembodiment, amplitude modulation is used; for instance, the amplitude ofthe driving signals ϕ and /ϕ can be varied, or the positive and negativerails of the driver circuit (e.g., V+ and V−) can be varied to controlthe amplitude. In another embodiment, phase modulation is used. Forinstance, in digital signal transmission, one phase corresponds to bitvalue 0, an opposite phase corresponds to bit value 1, and the phaseshifts represent transitions. Oscillator 504 can include a switchcircuit that either directly connects or cross-connects the drivingsignals ϕ and /ϕ to the inputs of a driver circuit. Combinations offrequency modulation, amplitude modulation, and/or phase modulation mayalso be used as desired.

In some embodiments, the transmitter may transmit a “packet” thatincludes a unique identifier for the identifier, which in turn is forthe composition with which the identifier is associated. The uniqueidentifier may also provide information from the remote device (e.g.,the identity of the active agent (i.e., annotation information)). Othertechniques for distinguishing different signals may also be used,including: operating different transmitters in different frequencybands, allowing each transmitter to be identified by its frequencyand/or configuring different transmitters to transmit at different (andknown) times, allowing the transmitter to be identified by when ittransmits.

Additional Components

Depending on the particular embodiment, the identifier may include anumber of different additional components. Some components of interestinclude, but are not limited, those reviewed below.

Power Enhancers

Where the activator is a power source that is turned on upon contactwith a target physiological site, in certain embodiments, circuits forenhancing or boosting voltage output of the power source, e.g., battery,are provided, e.g., charge pumping circuits, charge doublers, etc. Suchvoltage enhancing elements may enhance the voltage output by at about2-fold or more, such as by about 5-fold or more.

Power Storage

In certain embodiments, the activation component includes a powerstorage element. For example, a duty cycle configuration may beemployed, e.g., where slow energy production from a battery is stored ina power storage element, e.g., in a capacitor, which then provides aburst of power that is deployed to the signal generation component. Incertain embodiments, the activation component includes a timing elementwhich modulates, e.g., delays, delivery of power to the signalgeneration element, e.g., so signals from different compositions, e.g.,pills, that are administered at substantially the same time are producedat different times and are therefore distinguishable.

Additional Features

In certain embodiments, the compositions are characterized by having oneor more of the following features. In certain embodiments, thecompositions include an identifier which employs a conductive near-fieldmode of communication in which the body itself is employed as aconductive medium. In such embodiments, the compositions includecircuitry that, when freed from the composition upon disruption of thecomposition (e.g., as described above) the circuitry comes into directcontact with the body and does not remain encapsulated or protected insome manner. In these embodiments, the signal is not a magnetic signalor high frequency (RF) signal. In certain embodiments, the systems areones that include a receiver which is stably associated with the body,e.g., implanted or topically applied to an external location, such thatthe systems are distinguished from those in which an external devicethat is not stably associated with the body is employed to collect data.In certain embodiments, the compositions do not include an imagingsystem, e.g., camera or other visualization or imaging element, orcomponents thereof, e.g., CCD element, illumination element, etc. Incertain embodiments, the compositions do not include a sensing element,e.g., for sensing a physiological parameter, beyond the activator whichdetects contact with the targeted physiological site. In certainembodiments, the compositions do not include a propulsion element. Incertain embodiments, the compositions do not include a sampling element,such as a fluid retrieval element. In certain embodiments, thecompositions do not include an actuatable active agent delivery element,such as an element that retains an active agent with the compositionuntil a signal is received that causes the delivery element to releasethe active agent.

Identifier Fabrication

In certain embodiments of interest, the identifier element includes asemiconductor support component. Any of a variety of different protocolsmay be employed in manufacturing the identifier structures andcomponents thereof. For example, molding, deposition and materialremoval, e.g., planar processing techniques, such asMicro-Electro-Mechanical Systems (MEMS) fabrication techniques,including surface micromachining and bulk micromachining techniques, maybe employed. Deposition techniques that may be employed in certainembodiments of fabricating the structures include, but are not limitedto: electroplating, cathodic arc deposition, plasma spray, sputtering,e-beam evaporation, physical vapor deposition, chemical vapordeposition, plasma enhanced chemical vapor deposition, etc. Materialremoval techniques included, but are not limited to: reactive ionetching, anisotropic chemical etching, isotropic chemical etching,planarization, e.g., via chemical mechanical polishing, laser ablation,electronic discharge machining (EDM), etc. Also of interest arelithographic protocols. Of interest in certain embodiments is the use ofplanar processing protocols, in which structures are built up and/orremoved from a surface or surfaces of an initially planar substrateusing a variety of different material removal and deposition protocolsapplied to the substrate in a sequential manner.

FIGS. 11A to 13B are diagrams showing a method for fabricating anidentifier according to an embodiment of the invention. FIG. 11A depictsa cross-section of a semiconductor wafer, 121, processed by siliconfoundry such as IBM or Taiwan Semiconductor Manufacturing Company. Thetop surface of the wafer, 122, contains numerous electrical contactpads, 123, and an insulating dielectric layer, 124. The contact pads canbe Al but could also be Cu, Ti, or similar metal; the dielectric may bea combination of SiO₂ and Si₃N₄, but could be other insulators. In thefirst process step, shown in FIG. 11B, wafer 121 has been thinned fromthe back side via grinding or chemical/mechanical polishing to reducethickness to a desired thickness. A final thickness might be about 300μm but it can range from about 10 to about 1000 μm such as from about50-about 500.

FIG. 12A shows the second process step, in which a layer of corrosionresistant metal, 125, has been added to the front side of the wafer tocover the electrical contacts, 123. The typical metal is platinum butone could also use other corrosion resistant metals such as Au, Ti, Ir,or another platinum group metal. The corrosion resistant metal may bedeposited by physical vapor deposition, for example, and may be fromabout 0.05 to about 100 μm thick, such as from about 0.5 to about 5 μmthick. The metal 125 is formed into a desired pattern viaphotolithography and etching which are standard semiconductor processingtechniques.

FIG. 12B shows the deposition of the cathode material 126. Cathodematerials of interest include, but are not limited to: Cu or CuI, e.g.,as described above. They are deposited by physical vapor deposition,electrodeposition, or plasma deposition, among other protocols. Thecathode may be from about 0.05 to about 500 μm thick, such as from about5 to about 100 μm thick. The cathode shape is controlled by shadow maskdeposition, or photolithography and etching. Each chip may contain twoor more regions, 127 and 127A, of cathode material as desired.

Next anode material 128A is deposited as shown in FIG. 12C. Anodematerials of interest include, but are not limited: Mg, Zn, or otherelectronegative metals. Adhesion layer 128B may be necessary to helpanode material to adhere to the silicon. Typical adhesion layers for theanode are Ti, TiW, Cr or similar material. Anode material and theadhesion layer may deposited by physical vapor deposition,electrodeposition or plasma deposition. The cathode may be from about0.05 to about 500 μm thick, such as from about 5 to about 100 μm thick.

FIG. 13A shows the optional protection layer 129A which is deposited andpatterned. In some applications it may be advantageous to control therate of anode or cathode exposure to the electrolyte environment, so aninsulating layer may be deposited and patterned in such a way that ithas openings, 129B, of limited size. This way the solution reaches theanode or cathode material at a controlled rate. FIG. 13A illustrates theprotection layer on the front (cathode) side of the wafer but it couldbe also deposited on backside (anode side) of wafer. Typical materialsfor the protection layer are polyimide, or other photo definable polymerany of which may be spin coated or spray coated. Alternatively adielectric like SiO₂, SiC, or SiN may be deposited by physical vapordeposition or chemical vapor deposition.

The wafer is then singulated into individual die 115, 116, 117 as shownin FIG. 13B. Dicing can be accomplished by dicing with a diamond bladesaw or by reactive ion etching. These are standard silicon semiconductorprocessing techniques. As reviewed above, the chip dimensions may vary.As such, in certain embodiments, the chip (i.e., identifier) element isdimensioned to have a width ranging from about 0.05 mm to about 1 mm,such as from about 0.1 mm to about 0.2 mm; a length ranging from about0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and aheight ranging from about 0.1 mm to about 1 mm, such as from about 0.05mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm.

Specific Pill Embodiments

In further describing various embodiments of the compositions of theinvention, specific embodiments are now described in greater detail inview of the figures. FIG. 1 provides a diagrammatic, exemplaryrepresentation of a pill/capsule embodiment of the present invention, inwhich the composition is configured as an orally ingestiblepharmaceutical formulation in the form of a pill or capsule. The stomach12 of the patient 10 who ingests the composition 14 is shown. This“smart pill” is shown as it has traveled from the mouth 16 to inside 18the patient's stomach. Upon reaching the stomach, the pill/capsuleundergoes a dissolving process with both the mechanical action of thestomach and the various chemical materials in the stomach fluids, suchas hydrochloric acid and other digestive agents.

FIGS. 2A and 2B provide a more detailed view of the pill compositionshown in FIG. 1. FIG. 2A illustrates an identifier 20 disposed inside apill 14. Identifier 20 is present as an integrated circuit (IC). Thebackside (bottom) of circuit 20 is at least partially coated with afirst metal 21, and a portion of the front (top) of circuit 20 is coatedwith a different metal 22, allowing circuit 20 to be powered by reverseelectrolysis, e.g., as described above connection with FIG. 4. Also onthe top surface are two transmitter electrodes 23, 24.

When pill 14 is fabricated, the integrated circuit 20 is surrounded byat least one external layer that may include pharmacologically activeand/or inert materials in any combination. The external layer dissolvesin the stomach through a combination of the mechanical action of thestomach and the action of various chemical constituents (e.g.,hydrochloric acid) in stomach fluids.

As pill 14 is dissolved, areas of integrated circuit 20 become exposedto the stomach contents, which for present purposes can be regarded asan electrolyte solution. As dissolution of the pill exposes metal layers21 and 22, power is supplied to circuit 20, which begins to operate andcontinues to operate until metal layers 21 and 22 or the circuit itselfare sufficiently dissolved by digestive processes and acids to becomenon-functional. Eventually, the remains of the chip are excreted fromthe body.

In an alternative embodiment, the integrated circuit 20 is attached to,rather than encapsulated in, the pill 14. For instance, circuit 20 mightbe placed at one end of the pill as the pill is being prepared, in asoluble coating on the surface of the pill, or the like. In embodimentswhere circuit 20 is wholly or partially exposed, integrated circuit 20begins to operate sooner after the pill enters the stomach rather thanafter the pill dissolves.

In one embodiment, circuit 20 transmits a signal identifying pill 14.The identifier may indicate the type (active ingredient(s), brand, etc.)and/or dosage of pill 14 and may also provide a lot number, serialnumber, or similar identifying information that would allow particularpills to be traced, e.g., as reviewed above.

FIG. 2B is a block diagram of one embodiment of electronic circuit 20.In this embodiment, circuit 20 is a transmitter unit that sequentiallytransmits a predetermined series of address (identifier) bits usingfrequency shift keying, with a first oscillation frequency correspondingto bit value 0 and a second oscillation frequency corresponding to bitvalue 1. As described above, metal layers 21 and 22 supply power tocircuit 20. The power (not explicitly shown in FIG. 2B) is supplied toan oscillator 25, a counter 26, a readout circuit 27, and an electrodedriver 28 that drives transmitter electrodes 29A, 29B to transmit thesignal. Oscillator 25 may be of generally conventional design (e.g., aring oscillator) and is advantageously configured to operate in thequasi-electrostatic frequency region as described above. Oscillator 25generates a driving signal ϕ that oscillates between high and lowvoltage levels and an inverted driving signal /ϕ that is opposite inphase to driving signal ϕ. In one embodiment, oscillator 25 is avoltage-controlled oscillator (VCO) with an oscillation frequency thatdepends on a control voltage provided on a signal path 25A. Counter 26counts the oscillations of driving signals ϕ and /ϕ and provides thecurrent count to readout circuit 27. In one embodiment, counter 26 is aneight-bit counter of generally conventional design; other types ofcounters (including counters with different widths) may also be used.Readout circuit 27 is configured with a set of address (identifier) bits27A that are advantageously fixed, e.g., at the time circuit 20 isfabricated. As noted above, the bits can be unique to a particularinstance of pill 14 or common to a lot of pills fabricated under thesame conditions or common to all pills containing a particularpharmacological agent. Address bits 14 can be stored in nonvolatilestorage circuits of generally conventional design, and any number ofaddress bits (e.g., 8, 16, 32, 48, etc.) may be provided. Readoutcircuit 27 generates an oscillator control signal (e.g., a voltage) online 25A that controls the frequency of VCO 25. In one embodiment,readout circuit 27 is configured to select a current address bit, e.g.,based on the current count provided by counter 26, and to generate acontrol signal on signal line 25A that selects a frequency correspondingto the value of that bit. After some number of cycles (as determined bycounter 26), readout circuit 27 selects the next address bit andgenerates the corresponding control voltage on signal line 25A. Variousfrequencies may be used to represent the address bit values “1” and “0.”In one embodiment, frequencies of 100 kHz and 200 kHz may be used torepresent values “0” and “1,” respectively. Other values (e.g., 1 MHzand 2 MHz or 1 kHz and 5 kHz) may also be used. The chosen frequenciesadvantageously are well below the absorption modes of human tissues,which are typically above 400 MHz. As described above, VCO 25 generatescomplementary signals ϕ, /ϕ that oscillate at a frequency determined bythe control signal on signal line 25A. The signals ϕ, /ϕ are used tocontrol an electrode driver 28, which may be implemented, e.g., as shownin FIG. 6D. It should be noted that since electrodes 21 and 22 are incontact with stomach fluids when circuit 20 is operative, the near-fieldcomponent is coupled directly into the conductive medium of thepatient's body and can be detected by a suitably configured datacollector, e.g., as described below. In one embodiment, the collector isconfigured to log the received address (identifier) and the time ofreceipt. The data collector can also be configured to retransmit thisinformation to an external device, either in real time or while thepatient is in a medical facility. It will be appreciated that thetransmitter described herein is illustrative and that variations andmodifications are possible. For instance, other encoding schemes couldbe used to transmit the data; in one such embodiment, phase shift keyingrather than frequency keying is used. In some embodiments, multipleaddress bits can be encoded into a single symbol that is transmittedusing various keying schemes known in the art.

FIG. 3A provides a detailed depiction of an embodiment of a signalgeneration element 30 which labels the pharmaceutical material and isencapsulated in the center of the composition. Signal generation element30 is in the form of IC constructed from a silicon chip where variousfunctional elements, e.g., in the form of one or more layers ofcircuits, are disposed on a silicon substrate 31. The chip can befabricated using standard integrated circuit techniques. An example ofsuch a fabrication approach is a 0.5μ CMOS process made available by AMISemiconductor in Idaho, USA. Shown on the backside of the substrate, thebottom of the chip 31 is metal 1 32 which functions as one batteryelectrode and on the topside of the chip is metal 2 33 which functionsas the other battery electrode. Also on the top side of the chip 31 areelectrode 1 34 and electrode 2 35, which constitute a pair ofsignal-transmission electrodes.

In certain embodiments, electrode 1 34 and electrode 2 35 are fabricatedfrom a material that does not readily corrode in the stomachenvironment, e.g., they are fabricated from noble metals. Alternatively,in some cases the electrodes can be fabricated of a standard aluminum,such as that available from AMI Semiconductor. The criteria forelectrode material selection will be readily ascertainable by theordinary skilled artisan. That is, if the survival time of the electrodeis long enough for detection, it is suitable for use. Standard aluminummetals or other lower cost metals if used for electrodes 1 and 2 (34 and35) in appropriate applications allow a lower cost for the device. Insome cases dissolution of the electrodes, and thus extinction of thereporting signal, can provide a secondary indication of the fulldissolution of the pill and incorporated devices.

Metal 1 and metal 2 (32 and 33), in distinction to material selectionfor the electrode component of the inventive device, are two differentmetals. Metal 1 and metal 2 are selected so that the potential appliedto the silicon is a positive voltage on the top surface and a negativevoltage on the bottom surface. In this way the substrate is essentiallyat the same potential as the cathode, which can be the ground referencefor the circuits, and the top surface, with a Sift insulation layer, iscoupled to a positive voltage, referenced to that ground on the bottomside.

FIG. 3B provides a view of an alternative signal generation elementaccording to an embodiment of the invention. Instead of electrodes, thesignal generation element 30 depicted in FIG. 3B includes two antennae36 and 37 attached to silicon chip 31. Also shown are metals 1 and 2 (32and 33). The assembly 30 includes circuitry on a silicon chip 31 witheither two or four metal structures (32, 33, 36 and 37) attached to it.In embodiments where two different metals are employed, the two metalstructures serve as battery metals, that is metal 1 and metal 2 (32 and33). These metal structures can be provided in a variety of forms. Forinstance, in one embodiment, metal 1 and metal 2 are very thick platedelements on the surface of the chip, front and back (e.g., as shown inFIG. 3C described below). In another embodiment, metal 1 and metal 2 arerelatively long wires that are simply bonded to the chip at some point,e.g., as shown in FIG. 3B. Metal 1 and metal 2 in some cases areinsulated. In this case, the erosion occurs at the tip and thenpropagates towards the chip 31. The erosion as it dissolves in thesolution starts at the end of the wire and gradually work its way towardthe chip 31. This configuration improves battery life. In anotherconfiguration, a metal is plated up on the front and back of the chip,and then the surface disappears. The two wires can also be employed asantennae. In one configuration, a perpendicular pair of antennae (36 and37) is provided. In this implementation, there would be two other metalstructures which are typically of the same material. This material canbe selected from a variety of metals, such as platinum or gold. Thesemetal structures are attached to the chip and extend some dimension awayfrom the chip. Typically these structures are on the order of amillimeter to a centimeter combined length. In some configurations, asignificant portion of the metal structures are insulated so that thedipole created is of maximum dimension. In other configurations, justthe battery metals perform that dipole function, e.g., as describedbelow in connection with FIG. 3C, or a separate antenna is provided.

In certain embodiments, the signal generation element does not includeantennae and instead uses battery components as antennae, such as shownin FIG. 3C. In FIG. 3C, signal generation element 30 includes siliconsupport layer 31 positioned between metal 1 layer 32 and metal 2 layer33. Also shown is circuitry layer 38. In such embodiments, when a switchon the chip, e.g., in the circuitry layer, is closed, a current isproduced between the two metals of the battery, which is then detected.In certain embodiments, a membrane larger then chip which defines a pathfor the current to travel is provided.

Yet another embodiment of a battery which is activated upon contact witha physiological fluid is shown in FIGS. 3D and 3E. In the structureshown in these figures, the battery comprises top and bottom portionseach supporting an electrode, where the top and bottom portions can bebrought together to produce a structure comprising a volume bounded byopposing first and second electrodes, where the volume may be filledwith an electrolyte, e.g., physiological fluid, when active. FIG. 3Dprovides a representation of a bottom portion 31A of the battery inwhich material 1 32A is deposited into a recessed chamber 33A on top ofa substrate (e.g., silicon chip) 34A. Recessed chamber 33A has one ormore ends open to allow electrolyte to enter. Material 2 35A isdeposited on a separate substrate 36A to produce a second portion 37A,which is then bonded, e.g. by bonds 38A and 38B, to the chip in a “flipchip” type process. All processing can be done at the wafer scale. Wheredesired, the openings of the recessed chamber are filled with adegradable material, e.g., with a polymer, to control how quickly thebattery is activated. Substrates 34A and 36A for materials 34A and 35Acan be silicon, metal, or polymer/plastic. In certain embodiments, thestructure shown in FIGS. 3D and 3E is a battery where the firstelectrode is deposited into a recessed chamber on the top of the chip.The recessed space has one or two open ends to allow electrolyte flow.The second electrode is deposited on a separate substrate (e.g. asilicon wafer, a metal film or a polymer film), then bonded on top ofthe wafer with the chips on it in a “flip-chip” type process. Theprocessing is done at a wafer scale and the cells diced as usual. Theadvantages of this configuration include: protection of the electrodesurfaces from being blocked by components present in the stomach or thestomach lining itself; prevention of contact between any speciesgenerated on the battery (e.g., Cu) and the stomach lining that couldhave toxicity risks; 3) provision of uniform consumption of electrodematerials across the electrode surface and more uniform currentdistribution between the electrodes.

FIG. 4 provides a diagrammatic representation of the events which occurwhen the pill is ingested and dissolved to the point that some of thepill has been chemically and/or physically eroded away. Metal 1 andmetal 2 (32 and 33) are now in an ionic solution 39. This creates a lowvoltage (V−) and a high voltage (V+) as applied to an electronic circuit40. The two outputs of that electronic circuit 40 are E0 41 and E1 42,which are the signal-transmission electrodes on the top surface. In analternate embodiment no shown in FIG. 4 where the signal generationelement 30 includes a single electrode, the output is E0 41.

FIG. 5 shows a similar arrangement as in FIG. 4. However, instead ofhaving two electrodes as the output, a coil is provided. Metal 1 andmetal 2 (32 and 33) are applied to the electronic circuit 40 of signalgeneration element 30. The outputs of the electronic circuit 40 arecoupled to a coil 43. This configuration provides that a battery iscreated by metal 1 and metal 2 (32 and 33) when exposed to ionicsolution. This battery drives the circuit 40, which creates anoscillating frequency. This oscillating current goes through the coiland generates a RF magnetic signal. Unlike near-field quasi-staticelectrical signals, which may suffer from significant attenuationthrough body tissues, the RF magnetic signal can be transmitted throughbody tissues with less attenuation. The RF magnetic signal is thenpicked up by an external or internal receiver device that has amagnetic-signal detection mechanism. If a broadcast is provided at ahigh enough frequency, a pager-like device that is worn by the patientwill detect whenever a pill is ingested.

FIG. 6B shows the detail of one implementation of an electronic circuitthat can be employed in a signal generation element. On the left sideare the two battery electrodes, metal 1 and metal 2 (32 and 33). Thesemetals, when in contract with an electrolyte, form a battery and providepower to an oscillator 61, in this case shown as a schematic. The metal1 32 provides a low voltage, (ground) to the oscillator 61. Metal 2 33provides a high voltage (V_(high)) to the oscillator 61. As theoscillator 61 becomes operative, it generates a clock signal 62 and aninverted clock signal 63, which are opposites of each other. These twoclock signals go into the counter 64 which simply counts the number ofclock cycles and stores the count in a number of registers. In theexample shown here, an 8 bit counter is employed. Thus, the output ofcounter 64 begins with a value of “00000000,” changes to “00000001” atthe first clock cycle, and continues up to “11111111.” The 8-bit outputof counter 64 is coupled to the input of an address multiplexer (mux)65. In one embodiment, mux 65 contains an address interpreter, which canbe hard-wired in the circuit, and generates a control voltage to controlthe oscillator 61. Mux 65 uses the output of counter 64 to reproduce theaddress in a serial bit stream, which is further fed to thesignal-transmission driving circuit. Mux 65 can also be used to controlthe duty-cycle of the signal transmission.

In one embodiment, mux 65 turns on signal transmission only onesixteenth of the time, using the clock counts generated by counter 64.Such a low duty cycle conserves power and also allows other devices totransmit without jamming their signals. The address of a given chip canbe 8 bits, 16 bits or 32 bits. Typically, more than 8 bits will be usedin a product because there are so many different types ofpharmaceuticals. Each pharmaceutical will have its own specific address.

The present invention also allows the possibility that, whereappropriate, each pharmaceutical batch can be provided with a batchspecific address. This allows identification of where the pill was made,when the pill was made, and in what batch it was made. In some cases,each pill will have a unique identifier. This would be particularlyuseful when drugs are more likely to be subsequently stolen or usedillicitly, and thus should be tracked, or where questions ofcontamination may arise.

According to one embodiment, mux 65 produces a control voltage, whichencodes the address serially and is used to vary the output frequency ofoscillator 61. By example, when the control voltage is low, that is,when the serial address bit is at a 0, a 1 megahertz signal is generatedby the oscillator. When the control voltage is high, that is, when theaddress bit is a 1, a 2 megahertz signal is generated the oscillator.Alternately, this can be 10 megahertz and 20 megahertz, or a phase shiftkeying approach where the device is limited to modulating the phase. Thepurpose of mux 65 is to control the frequency of the oscillator or an ACalternative embodiment of the amplified signal of oscillation.

The outputs of mux 65 are coupled to electrode drive 66 which can drivethe electrodes to impose a differential potential to the solution, drivean oscillating current through a coil to generate a magnetic signal, ordrive a single electrode to push or pull charge to or from the solution.

In this manner, the device broadcasts the sequence of 0's and 1's whichconstitute the address stored in mux 65. That address would be broadcastrepeatedly, and would continue broadcasting until metal 1 or metal 2 (32and 33) is consumed and dissolved in the solution, when the battery nolonger operates.

FIG. 7 is an alternate embodiment of the present invention. Thisimplementation of the circuit 70 shows the oscillator 71 and a counter72. The mux 73 takes 5 bits from counter 72 as its input. On the upperright corner of FIG. 7 is an exemplary circuit diagram for thesignal-transmission electrode driver. Two CMOS invertors respectivelytake the clock and inverted clock signals as their inputs, and driveselectrodes e0 and e1.

FIG. 8 provides one implementation of an oscillator 80. In this case,V_(control) 81 basically controls the amount of voltage driving theoscillator 80. When V_(control) is low, a 20,000 ohm resistor 82separates Vow 83, which is the low power-supply voltage, and theoscillator control line, V_(osc) control 84. When V_(control) is high,the V_(osc) control goes to Vow, putting the maximum voltage across theoscillator circuitry and resulting in a higher frequency coming out ofthe clock signal and the inverted clock signal (85 and 86).

FIG. 9 shows a simple trickle or asynchronous counter which has in thiscase four flip flops with some simple inverters that simply count allthe way up and then start over again back to zero, and start countingall the way up again. In one embodiment, a multiplexer can take AO andA1, A2, A3, as its address inputs and can compare these inputs with astored address, and then have the stored address output as theoscillator control signal.

As indicated above, in certain embodiments the signal generation elementmay include a single electrode, and therefore have a monopoleconfiguration. In one embodiment of the present invention, as shown inFIG. 10, a three terminal, monopole signal generation element 100 isprovided. In this embodiment, the signal generation element 100 of thepill has one electrode 101 which is capacitively coupled to chip 107.Two metal electrodes 103 and 102 constitute the electrodes for thebattery, which provides power for the signal generation element 100.Electrodes 102 and 103 are coupled to the chip 107 through two resistors104 and 105, and an optional storage capacitor 106. In one embodiment,electrode 102 is the ground and electrode 103 provides V_(high) for thesignal generation element. Electrode 101 is the output of the mono polesignal generation element. During operation, electrode 101 will pushcurrent into and out of body's fluid at a high frequency. A receiverwill detect the pushing and pulling of that charge out of the body'sfluids. Note that the biggest difference between this configuration andthe configuration described previously is that this configurationprovides a mono pole. When chip 107's output changes, capacitor 108forces the potential on electrode 101 to change instantly, which resulta corresponding change in the potential of the body. A receiver that isin contact of the body can thereby detect a large transient voltagechange.

This inventive design produces an alternating current into and out ofthe body which is detected by a receiver (not shown). The outputcoupling capacitors may be optional. However, the presence of thesecapacitors prevents any DC currents and forces an AC signal.

FIG. 14 shows the multiplexer and the addressing system 73 of thecircuitry of the signal generation element of FIG. 7. In this case,there are two 4 bit muxes (141 and 142) and a 1 bit mux 143, wherein the1 bit mux 143 takes the outputs of the two 4 bit muxes 141 and 142 asits input. Each input port of muxes 141 and 142 is coupled to either thehigh voltage V_(high) or the low voltage V_(low). This configuration ofthe present invention will allow for a 32 bit number, which ishard-wired to the 32 inputs of the two muxes, to be converted to amultiplexed serial output 144. As the counter goes through the 5 bits ofcounting, the output of mux 144 sequentially selects the inputs of muxes141 and 142. When the 5 bit counter reaches “11111,” the sequence willstart over from the beginning again. This way the 16 bit address isrepeatedly sent. An alternative approach is to send 16 bits of zeros and16 bits of address alternatively, so that the receiving circuitry can bewaken up and synchronized.

FIG. 15 shows a detail of the 4 bit mux 141 of the system shown in FIG.14. The 4 bit mux is constructed from 4 levels of 1 bit muxes.

FIG. 16 shows the 1 bit mux in detail that makes up the 4 bit mux 141.

FIG. 17 is an additional mono pole embodiment 170 of a signal generationelement. The biggest difference from the prior described embodiments isthat a current source 171 is placed in series with the power supplycreated by M1 172 and M2 173. This creates a DC current between M1 172and M2 173. This DC current does not compete with the AC signalgenerated by the electrode 174. This DC current will then go to one oranother capacitor (175 and 176) and would either charge up the electrodeor charge up another capacitor. The concept behind this embodiment is tohave a DC current created between M1 and M2 and an AC signal generatedat the single electrode. Coupling capacitor 176 is optional.

FIG. 18A is an exemplary schematic diagram of a signal-transmissiondriver circuit. This circuit is based on an 8-pin 555 timer chip. As isshown on FIG. 18A, the pin designations of the 555 timer chip are asfollows: pin 1 is the ground; pin 2 is the trigger, pin 3 is the output,pin 4 is reset, pin 5 is the control voltage, pin 6 is the threshold,pin 7 is discharge, and pin 8 is the power supply to the chip V_(dd).The output pin and the ground pin are capacitively coupled to twotransmission electrodes, respectively. During operation, this circuittransmits a signal at a fixed frequency.

FIG. 18B1 to 18B2 is an exemplary schematic diagram of a receivercircuit. Shown on the upper left portion of the diagram is a front-endamplification stage, which receives the signal through a pair ofelectrodes and performs differential amplification to the signal usingan instrumentation amplifier. In the middle portion of the diagram is acascaded four-stage filter. In one embodiment, the first two stages arehigh-pass filters with a cut-off frequency higher than 1 KHz, such as acut-off frequency at approximately 10 KHz. The high-pass filter removesthe low-frequency noises and interferences, such as the 60 Hz power-linenoise. The last two stages are low-pass filters with a cut-off frequencylower than 500 KHz, such as a cut-off frequency at approximately 200KHz. The low-pass filters can remove high-frequency noises andinterferences. The filtered and amplified signal is fed to an LED, as isshown on the lower left portion of the diagram. When a signal isdetected, the LED is lit indicating presence of the signal.

The device described above generally includes two circuits: one is alogic circuit that generates the address bit sequence, and one is adriver circuit that drives the transmission electrodes based on theaddress bit sequence. The power-consumption characteristics of these twocircuits are different. Typically, the logic circuit requires a highvoltage power supply, e.g., a 1.2 V power supply, to switch the CMOScircuits. However, the current drawn through the logic circuit isrelatively small. For example, in one embodiment, the current drawnthrough the logic circuits is approximately 5 μA.

On the other hand, the driver circuit may draw a much larger current,because of the power it requires to transmit a sufficiently detectablesignal. Consequently, the voltage of the power supply can be pulled downto a lower level. For example, the driver circuit can draw 100 μA andpull the battery voltage down to 0.5 V.

Because the area of the battery electrodes can be limited due to thesize constraint of the device, the interference between the two circuitswith regard to power supply may be significant. As a result, the drivercircuit could pull the battery voltage down to a point that makes thelogic circuit inoperable. One embodiment of the present invention uses asplit battery configuration to decouple the power supplies for the logicand driver circuits.

FIG. 19 shows one exemplary split (i.e., segmented) battery design. Twobattery electrodes 193 and 194, which are made from copper iodine,constitute the battery anodes for the logic circuit 191 and drivercircuit 192, respectively. Effectively, electrodes 193 and 194 form twoseparate batteries with a shared common magnesium cathode 195. In thisway, the driver circuit 192 can draw sufficient current to drivetransmission electrodes 196 without significantly impairing the powersupply for the logic circuit 191.

During operation, driver circuit 192 draws a current from the batteryformed by electrodes 194 and 195, and pushes this current throughtransmission electrodes 196 into the body. In a further embodiment, thedevice can avoid the use of separate transmission electrodes by usingthe battery electrodes for transmission. FIG. 20 shows such aconfiguration. The driver circuit 206 essentially contains a switchcoupled between the anode 204 and the cathode. This switch can be turnedon or off by the address signal from the logic circuit 201. When theswitch is turned on, the battery for the driver circuit is effectivelyshort-circuited within the chip. Consequently, a current 207 flowsthrough the body from the cathode to anode 204. The resistance of thebody tissue can thereby generate a voltage difference, which can bereadily detected by, for example, a differential amplifier.

In some cases, the size of the cathode could be limited, resulting incoupling between the power supplies for the logic and driver circuitseven with split anodes. According to one embodiment, as is shown in FIG.21, the cathode can also be split to further decouple the two powersupplies. Here, two separate magnesium electrodes 211 and 212 serve asseparate cathodes for the two batteries respectively serving the logicand driver circuits. The coupling between the two circuits can thus beminimized.

In a further embodiment, the battery electrodes for the driver circuitcan be detached from the chip and coupled to the driver circuit throughtwo external wires, as is shown in FIG. 22. The battery electrodes forthe logic circuit, on the other hand, can still be deposited on the chipto provide high-voltage power supply to the logic circuit. The externalwires 221 and 222, which can be approximately 1 cm long each, form along dipole and can provide attendant signal amplification. As a result,the effectiveness of the transmission is not limited by the size of thechip. In one embodiment, the wires are initially folded within a pilland can unfold when the pill is digested.

Methods of Making Compositions

A variety of manufacturing protocols may be employed to producecompositions according to the invention. In manufacturing the subjectcompositions, a signal generation element is stably associated with thepharmaceutical dosage from in some manner. By stably associated is meantthat the signal generation element and the dosage form to do separatefrom each other, at least until administered to the subject in needthereof, e.g., by ingestion. The signal generation element may be stablyassociated with the pharmaceutical carrier/active agent component of thecomposition in a number of different ways. In certain embodiments, wherethe carrier/active agent component is a solid structure, e.g., such as atablet or pill, the carrier/active agent component is produced in amanner that provides a cavity for the signal generation element. Thesignal generation element is then placed into the cavity and the cavitysealed, e.g., with a biocompatible material, to produce the finalcomposition. For example, in certain embodiments a tablet is producedwith a die that includes a feature which produces a cavity in theresultant compressed tablet. The signal generation element is placedinto the cavity and the cavity sealed to produce the final tablet. In avariation of this embodiment, the tablet is compressed with a removableelement, e.g., in the shape of a rod or other convenient shape. Theremovable element is then removed to produce a cavity in the tablet. Thesignal generation element is placed into the cavity and the cavitysealed to produce the final tablet. In another variation of thisembodiment, a tablet without any cavity is first produced and then acavity is produced in the tablet, e.g., by laser drilling. The signalgeneration element is placed into the cavity and the cavity sealed toproduce the final tablet. In yet other embodiments, a tablet is producedby combining the signal generation element with subparts of the tablet,where the subparts may be pre-made subparts or manufacturedsequentially. For example, in certain embodiments tablets are producedby first making a bottom half of the tablet, placing the signalgeneration element on a location of the bottom half of the tablet, andthen placing top portion of the tablet over the bottom half and signalgeneration element to produce the final desired composition. In certainembodiments, a tablet is produced around a signal generation elementsuch that the signal generation element is located inside of theproduced tablet. For example, a signal generation element, which may ormay not be encapsulated in a biocompatible compliant material, e.g.,gelatin (to protect the signal generation element), is combined withcarrier/active agent precursor, e.g., powder, and compressed or moldedinto a tablet in a manner such that the signal generation element islocated at an internal position of the tablet. Instead of molding orcompressing, the carrier/active agent component is, in certainembodiments, sprayed onto the signal generation element in a manner thatbuilds up the tablet structure. In yet another embodiment, the activeagent/carrier component precursor may be a liquid formulation which iscombined with the signal generation element and then solidified toproduce the final composition. In yet other embodiments, pre-madetablets may be fitted with the signal generation element by stablyattaching the signal generation element to the tablet. Of interest areprotocols that do not alter the properties of the tablet, e.g.,dissolution etc. For example, a gelatin element that snap fits onto oneend of a tablet and has the chip integrated with it is employed incertain embodiments. The gelatin element is colored in certainembodiments to readily identify tablets that have been fitted with thesignal generation element. Where the composition has a activeagent/carrier composition filled capsule configuration, e.g., such as agelatin capsule filled configuration, the signal generation element maybe integrated with a capsule component, e.g., top or bottom capsule, andthe capsule filled with the active agent/carrier composition to producethe final composition. The above reviewed methods of manufacture aremerely illustrative of the variety of different ways in which thecompositions of the invention may be manufactured.

Systems

Also provided are systems that include the subject compositions. Systemsof the subject invention include, in certain embodiments, one or moreactive agent containing compositions, e.g., as reviewed above, as wellas a signal detection component, e.g., in the form of a receiver. Thesignal detection component may vary significantly depending on thenature of the signal that is generated by the signal generation elementof the composition, e.g., as reviewed above.

In certain embodiments, the signal detection component is an implantablecomponent. By implantable component is meant that the signal detectioncomponent is designed, i.e., configured, for implantation into asubject, e.g., on a semi-permanent or permanent basis. In theseembodiments, the signal detection component is in vivo during use. Inyet other embodiments, the signal detection component is ex vivo, bywhich is meant that the detection component is present outside of thebody during use. In certain of these embodiments, as developed ingreater detail below, either separate from or integrated with the exvivo detection component may be a dosage dispenser element, e.g., fordispensing dosages of the compositions based on signal detected from thesignal generation element of the detector. Such features may also bepresent in implantable detection components, e.g., to provide a closedloop administration system that administers a subsequent dosage based oninput about ingestion of a previous dosage.

As reviewed above, in certain embodiments the signal generation elementof the composition is activated upon contact with a target body site. Incertain of these embodiments, the signal detection component isactivated upon detection of a signal from the signal generation element.In certain of these embodiments, the composition generates anintermittent signal. In certain of these embodiments, the detectionelement is capable of simultaneously detecting multiple compositions.

The signal detection component may include a variety of different typesof signal receiver elements, where the nature of the receiver elementnecessarily varies depending on the nature of the signal produced by thesignal generation element. In certain embodiments, the signal detectioncomponent may include one or more electrodes for detecting signalemitted by the signal generation element. In certain embodiments, thereceiver device will be provided with two electrodes that are dispersedat some distance. This distance allows the electrodes to detect adifferential voltage. In certain embodiments, the first electrode is incontact with an electrically conductive body element, e.g., blood, andthe second electrode is in contact with an electrically insulative bodyelement relative to said conductive body element, e.g., adipose tissue(fat). In an alternative embodiment, a receiver that utilizes a singleelectrode is employed. In certain embodiments, the signal detectioncomponent may include one or more coils for detecting signal emitted bythe signal generation element. In certain embodiments, the signaldetection component includes an acoustic detection element for detectingsignal emitted by the signal generation element.

For those embodiments where the signal generated by the identifier is anear-field conductive signal, e.g., as reviewed above, the receiver ofthe present systems may also be viewed as “data collectors.” As usedherein, a “data collector” is any device equipped with receiving antennato detect the potential differences created in the body by a transmitteras described above, thus receiving the information transmitted. A datacollector may handle received data in various ways. In some embodiments,the collector simply retransmits the data to an external device (e.g.,using conventional RF communication). In other embodiments, the datacollector processes the received data to determine whether to take someaction such as operating an effector that is under its control,activating a visible or audible alarm, transmitting a control signal toan effector located elsewhere in the body, or the like. In still otherembodiments, the data collector stores the received data for subsequentretransmission to an external device or for use in processing ofsubsequent data (e.g., detecting a change in some parameter over time).It is to be understood that data collectors may perform any combinationof these and/or other operations using received data.

While the receiving antenna is advantageously inside the patient or incontact with the patient's skin, it is not required that data collectorbe entirely internal to the patient. For instance, a watch or belt wornexternally and equipped with suitable receiving electrodes can be usedas a data collector in accordance with one embodiment of the presentinvention. The data collector may provide a further communication pathvia which collected data can be extracted by a patient or health carepractitioner. For instance, an implanted collector may includeconventional RF circuitry (operating, e.g., in the 405-MHz medicaldevice band) with which a practitioner can communicate, e.g., using adata retrieval device, such as a wand as is known in the art. Where thedata collector includes an external component, that component may haveoutput devices for providing, e.g., audio and/or visual feedback;examples include audible alarms, LEDs, display screens, or the like. Theexternal component may also include an interface port via which thecomponent can be connected to a computer for reading out data storedtherein.

In some embodiments, the data collector is implanted. For instance, asnoted above, pacemaker leads provide a suitably sized receiving antenna.Typical pacemakers include a control unit (referred to as a “can”) thatincorporates logic circuits configured to perform various datacollection and processing operations. The can is also connected to RFtransmitter/receiver circuitry that allows communication between thepacemaker and an external wand operated by a health care practitioner.Thus, where the patient has a pacemaker, leveraging the existing unit asa data collector may be an efficient choice.

In certain embodiments, the system further includes an element forstoring data, i.e., a data storage element. Typically, the data storageelement is a computer readable medium. The term “computer readablemedium” as used herein refers to any storage or transmission medium thatparticipates in providing instructions and/or data to a computer forexecution and/or processing. Examples of storage media include floppydisks, magnetic tape, CD-ROM, a hard disk drive, a ROM or integratedcircuit, a magneto-optical disk, or a computer readable card such as aPCMCIA card and the like, whether or not such devices are internal orexternal to the computer. A file containing information may be “stored”on computer readable medium, where “storing” means recording informationsuch that it is accessible and retrievable at a later date by acomputer. With respect to computer readable media, “permanent memory”refers to memory that is permanent. Permanent memory is not erased bytermination of the electrical supply to a computer or processor.Computer hard-drive ROM (i.e. ROM not used as virtual memory), CD-ROM,floppy disk and DVD are all examples of permanent memory. Random AccessMemory (RAM) is an example of non-permanent memory. A file in permanentmemory may be editable and re-writable.

In certain embodiments, the data that is recorded on the data storageelement includes at least one of, if not all of, time, date, and anidentifier of each composition administered to a patient, where theidentifier may be the common name of the composition or a coded versionthereof. In certain embodiments, the data of interest includeshemodynamic measurements. In certain embodiments, the data of interestincludes cardiac tissue properties. In certain embodiments, the data ofinterest includes pressure or volume measurements.

The invention also provides computer executable instructions (i.e.,programming) for performing the above methods. The computer executableinstructions are present on a computer readable medium. Accordingly, theinvention provides a computer readable medium containing programming foruse in detecting and processing a signal generated by a composition ofthe invention, e.g., as reviewed above.

As such, in certain embodiments the systems include one or more of: adata storage element, a data processing element, a data display element,data transmission element, a notification mechanism, and a userinterface. These additional elements may be incorporated into thereceiver and/or present on an external device, e.g., a device configuredfor processing data and making decisions, forwarding data to a remotelocation which provides such activities, etc.

In certain embodiments, the signal detection component includes acardiac monitoring element, such as shown in the system of FIG. 1. FIG.1 shows a human 10 who has an implanted cardiovascular device “can” 8and a lead 6, which components are employed to monitor and detect thesignal emitted from pill 14. The monitoring device can be positioned inother locations as well, such as subcutaneously, in the heart, or in thewaist near the stomach, for example. Positioning may be suggested by aparticular application.

The inventive monitoring system can also be positioned as an externaldevice. By example, it could be positioned by a harness that is wornoutside the body and has one or more electrodes that attach to the skinat different locations. The inventive construct can be linked to aportable device, for example a watch that has one or two electrodesdispersed on the wrist. There are many places where such a receivingelectrode system could be placed and created such as, hearing aids thatbeep, necklace, belt, shoes (PZT-powered), or earrings.

As indicated above, in certain embodiments the systems include anexternal device which is distinct from the receiver (which may beimplanted or topically applied in certain embodiments), where thisexternal device provides a number of functionalities. Such an apparatuscan include the capacity to provide feedback and appropriate clinicalregulation to the patient. Such a device can take any of a number offorms. By example, the device can be configured to sit on the bed nextto the patient. The device can read out the information described inmore detail in other sections of the subject patent application, bothfrom pharmaceutical ingestion reporting and from psychological sensingdevices, such as is produced internally by a pacemaker device or adedicated implant for detection of the pill. The purpose of the externalapparatus is to get the data out of the patient and into an externaldevice. One feature of external apparatus is its ability to providepharmacologic and physiologic information in a form that can betransmitted through a transmission medium, such as a telephone line, toa remote location such as a clinician or to a central monitoring agency.

In certain embodiments, the cardiac monitoring element includes aconduction velocity measurement element. In certain embodiments, thecardiac monitoring element includes a pressure sensor. In certainembodiments, the cardiac monitoring element includes a dimension sensor.

Additional physiological sensors with various designs have beendescribed in additional applications by some of the present inventors.These sensors can by used jointly with the present inventive systems. Inaddition, other applications by some of the present inventors describemultiplexing systems with which the present invention can be veryusefully employed in an interactive, synergistic manner.

This prior work by some of the present inventors describes the use ofdimension sensors to determine heart parameters in order to facilitateappropriate therapy intervention, such as resynchronization therapy.Using the present invention to determining the time of blood-streamabsorption of cardiac treatment pharmaceutical and correlating this withchanges produced in heart function sensed by those devices provideshighly valuable information for the clinician in titrating medicationsand providing synergy between pharmacological and electrophysiologicaltreatment.

Embodiments of the present invention can be used in various systems.Such systems may include various types of sensors. Such sensors andsystems have been described in various applications by some of thepresent inventors. These applications also describe multiplexing systemspreviously developed by some of the present inventors with which thepresent invention can be employed. These applications include: U.S.patent application Ser. No. 10/734,490 published as 20040193021 titled:“Method And System For Monitoring And Treating Hemodynamic Parameters”;U.S. patent application Ser. No. 11/219,305 published as 20060058588titled: “Methods And Apparatus For Tissue Activation And Monitoring”;International Application No. PCT/US2005/046815 titled: “ImplantableAddressable Segmented Electrodes”; U.S. patent application Ser. No.11/324,196 titled “Implantable Accelerometer-Based Cardiac Wall PositionDetector; U.S. patent application Ser. No. 10/764,429, entitled “Methodand Apparatus for Enhancing Cardiac Pacing,” U.S. patent applicationSer. No. 10/764,127, entitled “Methods and Systems for Measuring CardiacParameters,” U.S. patent application Ser. No. 10/764,125, entitled“Method and System for Remote Hemodynamic Monitoring”; InternationalApplication No. PCT/US2005/046815 titled: “Implantable HermeticallySealed Structures”; U.S. application Ser. No. 11/368,259 titled:“Fiberoptic Tissue Motion Sensor”; International Application No.PCT/US2004/041430 titled: “Implantable Pressure Sensors”; U.S. patentapplication Ser. No. 11/249,152 entitled “Implantable Doppler TomographySystem,” and claiming priority to: U.S. Provisional Patent ApplicationNo. 60/617,618; International Application Serial No. PCT/US05/39535titled “Cardiac Motion Characterization by Strain Gauge”. Theseapplications are incorporated in their entirety by reference herein.

Some of the present inventors have developed a variety of display andsoftware tools to coordinate multiple sources of sensor information.Examples of these can be seen in PCT application serial no.PCT/US2006/12246 titled: “Automated Optimization of Multi-ElectrodePacing for Cardiac Resynchronization” and filed on Mar. 31, 2006 andclaiming priority to U.S. Provisional patent applications “AutomatedTiming Combination Selection” and “Automated Timing CombinationSelection Using Electromechanical Delay”, both filed Mar. 31, 2005.These applications are incorporated in their entirety by referenceherein.

The above described systems are reviewed in terms of communicationbetween an identifier on a pharmaceutical composition and a receiver.However, the systems are not so limited. In a broader sense, the systemsare composed of two or more different modules that communicate with eachother, e.g., using the transmitter/receiver functionalities as reviewedabove, e.g., using the monopole transmitter (e.g., antenna) structuresas described above. As such, the above identifier elements may beincorporated into any of a plurality of different devices, e.g., toprovide a communications system between two self-powered devices in thebody, where the self-powered devices may be sensors, data receivers andstorage elements, effectors, etc. In an exemplary system, one of thesedevices may be a sensor and the other may be a communication hub forcommunication to the outside world. This inventive embodiment may take anumber of forms. There can be many sensors, many senders and onereceiver. They can be transceivers so both of these can take turnssending and receiving according to known communication protocols. Incertain embodiments, the means of communication between the two or moreindividual devices is the mono polar system, e.g., as described above.In these embodiments, each of these senders may be configured to taketurns sending a high frequency signal into the body using a monopolepulling charge into and out of the body which is a large capacitor and aconductor. The receiver, a monopole receiver is detecting at thatfrequency the charge going into and out of the body and decoding anencrypted signal such as an amplitude modulated signal or frequencymodulated signal. This embodiment of the present invention has broaduses. For example, multiple sensors can be placed and implanted onvarious parts of the body that measure position or acceleration. Withouthaving wires connecting to a central hub, they can communicate thatinformation through a communication medium.

Methods

In the methods of the subject invention, an effective amount of acomposition of the invention is administered to a subject in need of theactive agent present in the composition, where “effective amount” meansa dosage sufficient to produce the desired result, e.g. an improvementin a disease condition or the symptoms associated therewith, theaccomplishment of a desired physiological change, etc. The amount thatis administered may also be viewed as a therapeutically effectiveamount. A “therapeutically effective amount” means the amount that, whenadministered to an subject for treating a disease, is sufficient toeffect treatment for that disease.

The composition may be administered to the subject using any convenientmeans capable of producing the desired result, where the administrationroute depends, at least in part, on the particular format of thecomposition, e.g., as reviewed above. As reviewed above, thecompositions can be formatted into a variety of formulations fortherapeutic administration, including but not limited to solid, semisolid or liquid, such as tablets, capsules, powders, granules,ointments, solutions, suppositories and injections. As such,administration of the compositions can be achieved in various ways,including, but not limited to: oral, buccal, rectal, parenteral,intraperitoneal, intradermal, transdermal, intracheal, etc.,administration. In pharmaceutical dosage forms, a given composition maybe administered alone or in combination with other pharmaceuticallyactive compounds, e.g., which may also be compositions having signalgeneration elements stably associated therewith.

The subject methods find use in the treatment of a variety of differentconditions, including disease conditions. The specific diseaseconditions treatable by with the subject compositions are as varied asthe types of active agents that can be present in the subjectcompositions. Thus, disease conditions include, but are not limited to:cardiovascular diseases, cellular proliferative diseases, such asneoplastic diseases, autoimmune diseases, hormonal abnormality diseases,infectious diseases, pain management, and the like.

By treatment is meant at least an amelioration of the symptomsassociated with the disease condition afflicting the subject, whereamelioration is used in a broad sense to refer to at least a reductionin the magnitude of a parameter, e.g. symptom, associated with thepathological condition being treated. As such, treatment also includessituations where the pathological condition, or at least symptomsassociated therewith, are completely inhibited, e.g. prevented fromhappening, or stopped, e.g. terminated, such that the subject no longersuffers from the pathological condition, or at least the symptoms thatcharacterize the pathological condition. Accordingly, “treating” or“treatment” of a disease includes preventing the disease from occurringin an animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

A variety of subjects are treatable according to the present methods.Generally such subjects are “mammals” or “mammalian,” where these termsare used broadly to describe organisms which are within the classmammalia, including the orders carnivore (e.g., dogs and cats), rodentia(e.g., mice, guinea pigs, and rats), and primates (e.g., humans,chimpanzees, and monkeys). In representative embodiments, the subjectswill be humans.

In certain embodiments, the subject methods, as described above, aremethods of managing a disease condition, e.g., over an extended periodof time, such as 1 week or longer, 1 month or longer, 6 months orlonger, 1 year or longer, 2 years or longer, 5 years or longer, etc. Thesubject methods may be employed in conjunction with one or moreadditional disease management protocols, e.g., electrostimulation basedprotocols in cardiovascular disease management, such as pacingprotocols, cardiac resynchronization protocols, etc.; lifestyle, such adiet and/or exercise regimens for a variety of different diseaseconditions; etc.

In certain embodiments, the methods include modulating a therapeuticregimen based data obtained from the compositions. For example, data maybe obtained which includes information about patient compliance with aprescribed therapeutic regimen. This data, with or without additionalphysiological data, e.g., obtained using one or more sensors, such asthe sensor devices described above, may be employed, e.g., withappropriate decision tools as desired, to make determinations of whethera given treatment regimen should be maintained or modified in some way,e.g., by modification of a medication regimen and/or implant activityregimen. As such, methods of invention include methods in which atherapeutic regimen is modified based on signals obtained from thecomposition(s).

In certain embodiments, also provided are methods of determining thehistory of a composition of the invention, where the compositionincludes an active agent, an identifier element and a pharmaceuticallyacceptable carrier. In certain embodiments where the identifier emits asignal in response to an interrogation, the identifier is interrogate,e.g., by a wand or other suitable interrogation device, to obtain asignal. The obtained signal is then employed to determine historicalinformation about the composition, e.g., source, chain of custody, etc.

In yet other embodiments where the identifier is one that survivesdigestion, the methods generally include obtaining the signal generationelement of the composition, e.g., by retrieving it from a subject thathas ingested the composition, and then determining the history of thecomposition from obtained signal generation element. For example, wherethe signal generation element includes an engraved identifier, e.g.,barcode or other type of identifier, the engraved identifier may beretrieved from a subject that has ingested the composition and then readto identify at least some aspect of the history of the composition, suchas last known purchaser, additional purchasers in the chain of custodyof the composition, manufacturer, handling history, etc. In certainembodiments, this determining step may include accessing a database oranalogous compilation of stored history for the composition.

Utility

The present invention provides the clinician an important new tool intheir therapeutic armamentarium: automatic detection and identificationof pharmaceutical agents actually delivered into the body. Theapplications of this new information device and system are multi-fold.Applications include, but are not limited to: (1) monitoring patientcompliance with prescribed therapeutic regimens; (2) tailoringtherapeutic regimens based on patient compliance; (3) monitoring patientcompliance in clinical trials; (4) monitoring usage of controlledsubstances; and the like. Each of these different illustrativeapplications is now reviewed in greater detail below.

Monitoring Patient Compliance with Prescribed Therapeutic Regimens

As summarized above, one type of application in which the subjectcompositions and systems find use is in monitoring patient compliancewith prescribed therapeutic regimens. By monitoring patient complianceis meant tracking whether a patient is actually taking medication in themanner prescribed to the patient. As such, the present inventionprovides accurate data of when a pill has been taken and which pill hasbeen taken. This allows the precise determination of which pill wastaken at a specific point in time. Such monitoring capability assurespatients are taking the prescribed medication correctly. Thisinformation avoids the potential for over prescription of medicationsthat are not actually being taken. By example, if pain killers areintended to be administered to a patient, it is possible to verify withthe present invention that the patient did in fact take those painkillers in a certain period of time. This knowledge is an important toolin limiting the illicit sale of unconsumed drugs to an unintended party.In the case of cardio vascular pills, the clinician or care giver isable to verify that the amount of the drug was taken has been taken atapproximately the right point and time. Thus, the true efficacy of thedrug can be accurately evaluated. Proper administration and patientcompliance is especially critical in Alzheimer's, psychiatric, andalcohol aversion drugs, and in the treatment of rest home residents. Inthe case of accidental and other overdoses situations, the interveningclinician will be able to discern how far the ingestion has proceeded,and how many pills are involved.

In more complex embodiments of the present invention, correct, timelyingestion of the drugs will automatically trigger a prescription refillsignal which is forwarded to a pharmacy data system, and in some casesthe refill will be automatically delivered directly to the patient'shome, or released by a device in the patient's home some period of timelater. This feature is particularly valuable in patients withcompromised mental capacity and/or limited physical mobility.

The invention is particularly useful in complex administration regimens,such as when multiple pharmaceuticals are being taken, and confusion ismore likely to occur. The inventive pills can have multiple externallayers, with only correct dosage allowing dissolution and absorption ofthe pharmaceutical component. Specific indicators, such as electricalconduction velocity in the heart or electrolytic levels in the blood inresponse to pharmaceutical can also be titrated.

In certain embodiments, a patient can be alerted when the patient is insome way non-compliant with a given treatment regimen. For example, by asound, visual, or computer reminder, if the pharmacological regimen isnot being accurately adhered to, a reminder is provided. If thatreminder is not accurately responded to, the system can provide an alertto family members, caregivers, or clinicians in order to remedy the gapin treatment or overdose. The device may also automatically modify thedosage and timing of the regimen to compensate for prior non-standarddosing.

Tailoring Therapeutic Regimens Based on Patient Compliance

As summarized above, one type of application in which the subjectcompositions and systems find use is in tailoring therapeutic regimensbased on patient compliance. In such applications, data obtained aboutwhether a patient has or has not taken a particular dosage is employedto determine future dosages and/or timing of such dosages. In certainembodiments, data concerning patient compliance is combined withadditional data, e.g., sensed physiological data, to make customizedchanges or modifications to a given therapeutic regimen. By example,when data about dosage compliance obtained according to the invention isused in concert with other medical sensing devices, correlation betweendrug delivery, batch and dosage can be correlated to a physiologicalresponse. In this manner, optimal pharma-therapeutic regimens may beformulated by the clinician. By example, cardiac stimulating drugs canbe titrated to the most appropriate dosages, minimizing side effectssuch as cardiac muscle exhaustion and rebound effects among others, andoptimizing both dosage and timing for each individual patient.

Assessment of a range of alternate medications is made possible by thepresent invention without resort to awaiting overt clinical sequel oftreatment, many of which can be seriously adverse. By example, positiveeffects would be quickly ascertainable without being obscured by morerandom factors. Negative responses, such as changes in blood pressure,would become clearly evident as drug related or independent abovebackground physiologic variation.

In one clinical arena, the present invention allows, in concert withother sensing devices developed by some of the present inventors, themeasurement and assessment of the cardiac response to those medications.These co-employed sensing devices can be those enumerated below, amongothers. Other sensing technology, e.g., as mentioned above, developed bysome of the present inventors allows measurement of heart health andcardiac efficiency. Using these tools in concert with the presentinventive device, the clinician will be able to compare the response ofthe heart and body to the administered pharmaceutical. The data providedby the present invention can optionally be recorded over time. Therecording system records synchrony or conduction velocity of a signalgoing through cardiac tissue and how that is mediated by the presence ofa certain medication. This unique data is made possible by the presentinvention since it can determine electronically exactly when the pill orother medication was being absorbed into the body.

In more standard clinical environments, this unique data allows carefulselection and titration of drug administration without resort to moreovert physical symptoms to ascertain contraindications, efficacy, andoptimal dosage levels

The present invention provides a record for emergency room techniciansor doctors when a patient is admitted to a hospital so that thepatient's status can be accurately ascertained. Dosage events within thelast hour or day prior to admission, and the identity of the lastmedication, will be immediately available. As such, future therapeuticregimens can be made based on accurate records of patient drugmedication history.

In certain embodiments, the clinician obtains this information throughsimple interrogation of the implanted or portable device. This devicewould tell them without any uncertainty what pills have been taken. Asthe inventive technology becomes more wide spread, this data will becomemore regularly available. The present inventive microchips aresufficiently inexpensive such that when they are put into standardproduction, most or all pharmaceuticals will be fitted with them as amatter of course.

The patient monitoring capacity of the external reporting apparatus isan importation function which the inventive device can provide. Whencoordinated with internal or external physiologic sensing data, thedevice can read out the physiological response of the patient to theingestion of medication, and then transmit this information back to theclinician. The clinician can then modify therapy to optimaleffectiveness, as indicated by the new data in response to the modifiedtherapy, and so forth.

In more sophisticated embodiments of the present invention, the dosageadjustment function, within certain parameters, can be performed by anintelligence circuit in the apparatus. By example, for a blood pressuremedication, the patient takes their blood pressure pill. 20 minuteslater, the internal monitoring circuitry in the implantable deviceregisters a drop in blood pressure. The circuitry quantifies this drop,and transmits it to this bedside apparatus. The apparatus then canadjust the dosage of the pill to optimally treat the patient. Similarly,when the patient is connected to an IV, the dosage can be dispenseddirectly into the IV fluid. In certain embodiments, the closed-loopsystem is provided as a fully implantable device.

Current clinical practice for drug treatment optimization isconsiderably more limited than that which is available by use of thepresent inventive device. Currently, blood pressure medication treatmentis set at so many pills per day. Such a blunt dosage regime takes a longtime to optimize appropriately because the feedback loop is very slow.By contrast, with the present invention, the feedback loop ofphysiologic response to pharmaceutical dosage is very rapid and veryefficient. Ultimately, the present invention allows tailoring the drugdosages day to day, or even more finely, to account for change inactivity, change in physiological conditions in the patient, and otherdosage parameter.

In more sophisticated embodiments of the present invention,physiological reactions to specific dosages and time intervals wouldalso be continually monitored. In some embodiments, the level of drug inthe blood stream is monitored, allowing for individual and time of dayvariations in drug metabolism.

This aspect of the present invention effectively minimizes underdosingor overdosing the controlled substances, in some cases addressing thesechanges before they produce external symptoms apparent to the patient orclinician. The drug dosage can be automatically titrated so that, byexample, the smallest appropriate level to quell anxiety due to pain,other physiologic reactions to pain, or provide steady or graduallydiminishing blood levels of the drug would be dispensed. This feature ofthe present invention provides an automatic, appropriately gradual,weaning off of the drug, lessening the chance of serious addiction orsevere, adverse withdrawal reactions.

Clinical Trial Applications

An important application of the invention is to provide immediatefeedback of physiological data response to administration of apharmaceutical agent in clinical drug trails. A current challenge isthat the experimental drug is administered broadly to a populationwithout a comprehensive foreknowledge of which sub-groups within thispopulation are most likely to benefit from the treatment. Anotherchallenge is monitoring patient compliance with the treatment regimen,by determining if the tests subjects are taking the medicine asindicated. The later challenge is addressed in the sections above. Bothpatient non-compliance levels and actual response to drug ingestion canthus be determined. As such, compliance intervention can then beaddressed early in the study.

In certain embodiments of the present invention, clinical researchersare provided with immediate access to physiological data. The clinicalresearchers are able to identify the subset for which the drug is mostlikely effective from within the original test population of possibleparticipants in the trial. The example above of a patient receivingblood pressure medication and getting feedback immediately demonstrateshow effectiveness of a novel medicine can be quickly determined.

Upon administration of the first doses of medication to initial testsubjects, the clinical researchers are likely to find that some subjectsin the population respond to the medication and others do not. Thisimmediate feedback allows the administrator of the trail to excludethose patients who do not respond to the medication and target only thatsubgroup for which there is clear efficacy. This culling process allowsthe overall results of the trail to get a much higher effectivepercentage, because one is able to target the drug to the group for whomit is effective. It also avoids side effect challenges for subjects whowould not have a benefit balance to such risks.

As such, from this innovative data, the present invention provides theclinician an accurate dose response curve showing the response to thatmedication and the timing of the digestion of the pill. Such innovativedata has many applications. For instance, the clinician now has theability to determine which patients have no response to the medicine inthe pill. In a study situation, such patients can be removed from astudy or a test of the clinical utility of a certain medication. Thisability provides that only people who have a beneficial response to acertain medication are retained in the trail. This feature will improvethe efficacy of medications and to reduce the amount of medications thatpeople take that are not being useful. It may also be used in trials todetermine which patients actually consumed the medicine, and which didnot.

The present invention allows identification of physiological proxies forthe efficacy of a drug. By example, for a drug which has a long termadministration prior to the development of overt clinical changes, thereare typically certain short term physiological factors which appearimmediately after ingestion of the drug. By example, cancer medicationwhich requires many months to show an effect, can have shorter termindicia of its efficacy in one or a constellation of physiologicfactors. Changes, both local or throughout the whole body, in bloodpressure, body temperature, internal chemical enzymes or other factorswill serve as proxies for the longer term desired effects. A precisecorrelation of these factors with the time of the pills ingestionenhances the ability to find meaningful indicia.

With the very closely timed correlated response to the ingestion of thepill provided for the first time by the present innovation,demonstrating that a physiologic response is a result of the drugingestion rather than any of the other possibility confounding factors,is much more likely. This capacity of the present invention can serve asa partial or complete proxy for clinical trials.

The invention provides a way to determine very quickly whether a patientshould be taking the medication or not, whether it will be effective ornot, and allow its appropriate titration. Synergies between medications,both helpful and adverse, will also become more readily apparent.

Monitoring Usage of Controlled Substances

As reviewed above, in other embodiments of the inventive microchips, theidentifiers can be fitted with coils, susceptible of interrogationwithout being dissolved in the body. This is accomplished bytransmitting RF energy into the coil in such a way that the inquirerwill be apprised of the presence and identity of a pill before it isingested.

In an additional embodiment of the present invention, a “smart box” isprovided that can interrogate each pill and ascertain its address. Thebox can write a distinctive product number or product code so that everysingle pill ever made is provided with a unique identifier. Fuses, forexample, may be selectively destroyed so the addresses may be detectedelectrically or optically. Particularly in the case of controlledsubstances, such as a narcotic, this will be important in limiting theillegal used of previously legitimate medicines. The present inventionmakes it possible to identify precisely who bought such a pill from theauthorized pharmacist. This use of the present invention will rein inthe number of illicit uses of controlled substances on the market place.

An important application for the external apparatus aspect of thepresent invention is in monitoring and regulating the use of controlledpharmaceutical substances. A serious risk when patients are prescribedheavy narcotics for pain control is the possibility of addiction. In itssimplest analysis, addiction occurs from the ingestion of too much ofthe controlled medication by inadvertent overdosing, purposeful misuse,or through inexact dosage prescription. Additionally, as describedabove, individual serial number are provided on such pharmaceuticals totrack the legitimate distribution of the drug before the illicitdistribution of such drugs.

In one application of the present invention, a means for locking andregulating the dosage of a potential addictive drug is provided. Anexample of this capacity of the present invention is when a patienttakes their narcotic pill, in which the ingestion of the medication isregistered by the internal device. This information is thenautomatically transmitted to the external apparatus.

The inventive apparatus is so configured that only after the patient hastaken the pill and at the appropriate time has elapsed does thisaccessory apparatus dispense a further pill. In this manner, theaddiction rate for the drug is dramatically lowered by limiting legaldrug availability by dispensing exactly the prescribed dosage atprecisely the appropriate time interval.

The external apparatus can also be effectively employed in mandatorymedication forensic applications. For example, in the case of aconvicted criminal, the criminal can be required to take court orderedmedication as a condition of release from jail. Using the presentinvention, the court or probation officer has access to a real-timerecord of the administration of this drug as this information is fedback through the accessory apparatus to the appropriate official. Thereis a current trend towards court mandated psychotropic or chemicalsterilization drug maintenance for sex offenders which would beaddressed by this aspect of the present invention. This use of thepresent invention is analogous to house arrests where physical positionmonitoring bands are worn on the ankle of the offender.

Kits

Also provided are kits for practicing the subject methods. Kits mayinclude one or more compositions of the invention, as described above.The dosage amount of the one or more pharmacological agents provided ina kit may be sufficient for a single application or for multipleapplications. Accordingly, in certain embodiments of the subject kits asingle dosage amount of a pharmacological agent is present and incertain other embodiments multiple dosage amounts of a pharmacologicalagent may be present in a kit. In those embodiments having multipledosage amounts of pharmacological agent, such may be packaged in asingle container, e.g., a single tube, bottle, vial, and the like, orone or more dosage amounts may be individually packaged such thatcertain kits may have more than one container of a pharmacologicalagent.

Suitable means for delivering one or more pharmacological agents to asubject may also be provided in a subject kit. The particular deliverymeans provided in a kit is dictated by the particular pharmacologicalagent employed, as described above, e.g., the particular form of theagent such as whether the pharmacological agent is formulated intopreparations in solid, semi solid, liquid or gaseous forms, such astablets, capsules, powders, granules, ointments, solutions,suppositories, injections, inhalants and aerosols, and the like, and theparticular mode of administration of the agent, e.g., whether oral,buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal,intracheal, etc. Accordingly, certain systems may include a suppositoryapplicator, syringe, I.V. bag and tubing, electrode, etc.

In certain embodiments the kits may also include a signal receivingelement, as reviewed above. In certain embodiments, the kits may alsoinclude an external monitor device, e.g., as described above, which mayprovide for communication with a remote location, e.g., a doctor'soffice, a central facility etc., which obtains and processes dataobtained about the usage of the composition.

The subject kits may also include instructions for how to practice thesubject methods using the components of the kit. The instructions may berecorded on a suitable recording medium or substrate. For example, theinstructions may be printed on a substrate, such as paper or plastic,etc. As such, the instructions may be present in the kits as a packageinsert, in the labeling of the container of the kit or componentsthereof (i.e., associated with the packaging or sub-packaging) etc. Inother embodiments, the instructions are present as an electronic storagedata file present on a suitable computer readable storage medium, e.g.CD-ROM, diskette, etc. In yet other embodiments, the actual instructionsare not present in the kit, but means for obtaining the instructionsfrom a remote source, e.g. via the internet, are provided. An example ofthis embodiment is a kit that includes a web address where theinstructions can be viewed and/or from which the instructions can bedownloaded. As with the instructions, this means for obtaining theinstructions is recorded on a suitable substrate.

Some or all components of the subject kits may be packaged in suitablepackaging to maintain sterility. In many embodiments of the subjectkits, the components of the kit are packaged in a kit containmentelement to make a single, easily handled unit, where the kit containmentelement, e.g., box or analogous structure, may or may not be an airtightcontainer, e.g., to further preserve the sterility of some or all of thecomponents of the kit.

The following example is offered by way of illustration and not by wayof limitation.

EXPERIMENTAL Example 1

In the following experiment, a transmitter (Tx) and receiver (Rx), eachpowered by batteries and encased in a water-tight Rubbermaid™ container,are employed. The Tx and Rx float in a bath of saline, and an LED glowson the Rx when the Tx is placed in the bath. Both Tx and Rx arecompletely isolated from the outside world.

The Tx, representing the compositions of the present application, e.g.,a pill composition having an active agent and signal generation element,is an oscillator circuit based on a CMOS timer chip. It produces asquare wave at about 80 kHz of 3V amplitude from a Lithium battery. Atightly twisted pair of wires extends from the circuit, out of thecontainer, and into the bath. At the end of the twisted pair, the wiresare striped of insulation by about 1 mm and separated to form a dipoleantenna. The signal amplitude was found to scale linearly with theseparation distance characterizing this dipole. The signal was easilydetectable with this setup when the dipole was 5 mm in extent.

The Rx is a filtered amplifier circuit with outputs to detect thetransmitted signal. A square of copper, 10 cm on a side, was attached tothe bottom of the outside of the container and attached to the negativedifferential input of the circuit; this represents the pacing can. Abipolar pacing lead, about 40 cm long, was attached to the positivedifferential input of the circuit; the ring electrode was selected forthe input. The differential signal was coupled into the inputs of a gain100 instrumentation amplifier through 0.1 uF series capacitors. Theoutput of the instrumentation amplifier was fed into a 4-pole high-passfilter, with gain of 100 and cutoff frequency 5 kHz. This output was fedinto a 2-pole low-pass filter with gain 20 and cutoff frequency 100 kHz.Thus, the overall gain of the circuit is 200,000. This output signal isapplied across an LED and resistor in series, which glows when theoutput signal exceeds a few volts.

When not in the bath, the Rx LED was on all the time as it picked upinterference and power line noise from the environment. When the pacinglead was shorted to the mock can the LED turned off.

When placed in solution, the LED turned off. When the Tx was also placedin solution, the Rx LED turned on and the dependence on position andorientation was investigated. The intensity of the LED was found todepend on the cosine of the angle between the Rx and Tx dipole, with anull for perpendicular orientation and sign inversion as the sense ofthe dipole was reversed, as observed with an external oscilloscope. Theintensity of the LED was found to vary directly with position, with abright, saturated glow observed for spacing less than 5 cm and a dim,diffuse glow observed for the maximum spacing allowed by the bath, about50 cm.

The key to making the detection robust is differentiating the desiredsignal from spurious interference. Such was accomplished in thisexperiment by restricting the frequency band of sensitivity to between 5and 100 kHz. To the extent this band can be narrowed, the more robustthe system will be. The challenge here is to match the frequency of theTx and Rx circuits, in light of the fact that the Tx frequency may varyby 30% due to manufacturing variation. The Rx circuit can be very narrowthrough the use of a narrow bandpass or by using demodulation techniquesfrom the radio. The Rx circuit can be swept across a tuning frequencyrange to detect the presence of the pill. The presence of the pill canbe confirmed by encoding an unlikely bit sequence in the digitalinformation transmitted by the pill.

Two problems with this approach are that it consumes power from the Rxcircuit while it scans frequencies, and that synchronization withmultiple pills, which may burst the transmission of their codes, isdifficult. If the frequency of the Tx is known ab initio, as is possiblewith circuit trimming or advanced manufacturing processes, an elegantsolution to both these problems is presented. At the input to the Rxcircuit, a tuned LC oscillator matched to the Tx frequency will “ringup” when the desired signal is present. This power can be detected by asimple diode circuit, which serves as a trigger to turn the detectioncircuit on, greatly reducing the time it must draw current. This tunedinput also serves to narrow the bandwidth and reject spurious signals.

This above experiment demonstrates the ability to transmit and detectsignals through a synthetic biological medium. The Tx may be readilypowered off a chemical battery, such as a Pt/Mg system. Furthermore,digital information is readily encoded in the signal using a variety ofencoding techniques to eliminate errors and improve the overallreliability of the system.

Example 2

A transmitter according to the subject invention was set up as follows.The circuit was powered off a 9V battery and floated on a bath ofsaline. The circuit was an oscillator based on the TLC551 chip, a CMOSversion of the popular 555 timer. The oscillator was run at ˜7 kHz, witha duty cycle of perhaps 15%. The outputs of the oscillator were eachcapacitively coupled through 7 uF to a twisted pair, which wasterminated in a small “Y” shaped dipole, with the arms separated by ˜1mm, and ˜2 mm of bare wire exposed to the saline bath.

The signal was received through two Cu electrodes, each with ˜1 cm²exposed to the bath. This was routed to the input of a Stanford pre-ampoperated off batteries, set to a gain of 1000 with a pass band between 3kHz and 30 kHz. The output of the pre-amp was observed on a batterypowered oscilloscope.

A maximum signal of ˜200 μV referenced to the amplifier input wasobserved for an Rx electrode separation of ˜20 cm. A dipolar couplingstrength was observed, displaying a sinusoidal angular dependence, witha null in received signal for perpendicular orientation; phase inversionwas seen between parallel and anti-parallel orientations. The receivedsignal strength was seen to scale linearly with separation of the Rxelectrodes.

The above demonstrates that the signal is clearly detectable with properamplification and filtering. Furthermore, a capacitor on the input ofthe Rx amplifier is not necessary; as the same results were obtainedusing DC coupling on the input with a high-pass filter later in thesignal chain.

The above results also verified that the Tx can run off an Mg/Pt potatobattery.

Example 3

A prototype smart pill microchip, which broadcasts a fixed code usingfrequency shift keying, was first powered by a 1.5V AA battery. Theconductive signal was applied to a physiological saline bath with atwisted pair T-shaped dipole, approximately 1 cm across with 1 mm ofconductor exposed on each arm of the T. The signal was detected by twocopper electrodes, spaced approximately 10 cm apart, which feed into abattery powered, isolated differential pre-amp. The signal was observedon an oscilloscope. An oscillatory signal, clearly representative of thetransmitted data, was observed with a frequency of about 300 kHz and aninput-referenced amplitude of about 10 mV.

Furthermore, a dependence of the received signal strength on the cosineof the angle between the transmit and receive conductors, as ischaracteristic of a dipolar interaction, was observed.

A Mg—CuI water-activated battery, with each electrode having an exposedsurface area of ˜1 mm² was constructed. The Mg electrode was formed bysimply potting commercial grade Mg ribbon in epoxy and polishing the endflat with sandpaper. The CuI electrode was produced by first polishingthe end of Cu wire potted in epoxy.

Approximately 100 μm of Cu was then electroplated on the end of the Cuwire using standard techniques, with the parameters chosen to give alarge roughness coefficient, increasing the effective area of theelectrode. The surface of this plated Cu was then transformedelectrochemically to CuI by applying a potential corresponding to thepotential of the Cu+ ion in a solution of I− ions. In approximately 15min 40 mC of CuI was produced. The battery was demonstrated to have anopen cell voltage of ˜1.05V in a pH 2 solution, corresponding to theacidity of a typical stomach.

The CuI—Mg battery was connected to the power terminals of the chip, andthe output terminals were connected to the dipole conductor describedabove in a physiological saline bath. The battery was activated bydropping the electrodes in the bath, and a signal of amplitude ˜2 mV ata frequency of 20 kHz was observed for at least a minute.

Finally, the output terminals of the chip were shorted together,effectively configuring the chip for the 2-terminal operation describedabove. An output signal was observed, but its amplitude was much weaker,probably because of the decreased effective transmitter dipole length inthis configuration. That is, in the 4-terminal configuration, theeffective transmit conductor size is determined by the spacing betweenthe battery and dipolar T, which was several centimeters; in the2-terminal mode, the effective dipole length is reduced to theseparation between the Mg and CuI electrodes, which was less than 1 cm.The observed signal was perhaps a few hundred μV, and could bequantified using averaging to overcome an interfering signal amplifiedby the broadband receiver. More sophisticated detection schemes willhave little problem detecting such a signal reliably.

Example 4

A pill composition as described above prior to ingestion may be composedof two main components, an address generating logic circuit and a signaltransmission circuit. The address generation circuit is powered with lowcurrent adequate to the required tasks. However, if the voltage suppliedto the address generation circuit changes, the frequency of theoscillator therein will also change. This may produce changes in signaltransmission, introduce noise into the transmission, and cause otherundesired effects.

For design purposes, it is simpler to power the address generationcircuit with a constant voltage. However, in certain embodiments a morecomplex configuration may be desired. By example, when the transmissionstarts, the transmitter consumes considerable energy. As a result, thevoltage will drop because as more energy is consumed, the voltage of thepower source drops. The change in voltage will result in a change offrequency in the oscillator within the address generation circuit.

An example of this challenge in a different area of engineering is whena remote control device is made from a receiver and servos. By contrast,the receiver works permanently, and consumes low current in proportionto the servo which consumes a very large current. The servos work onlywhen a signal is transmitted to the remote site. In that case, the wholesystem consumes a relatively large amount of power when the servos startto work. When the servo starts to work, the voltage drops, and producessome noise. As a result, the stability of signal transmission iscompromised.

In order to avoid this problem, embodiments of the system are poweredwith two voltage sources. The receivers are powered with one battery,and the servos are powered with another battery. With thisconfiguration, whatever occurs in the servo does not affect thereceiver. As such, a more stable remote control results, therebyimproving the performance of the complete system.

In one embodiment, a common cathode is provided. There are also twopositive electrodes, A1 and A2. In this case, with the battery dividedinto two parts, one part of the battery will power the addressgeneration circuit, and the other will power the transmission circuit.This configuration provides a stable voltage to the address generationcircuit. When the transmitter section of the device is turned on, onlythe voltage on the transmitter will change, but no change of voltagewill occur in the address generation section of the device. Hence, thechanges will typically cause a change in signal amplitude, but not inthe frequency. As a result, the transition will be more stable, and thefrequency of RF transmission will be unaffected, or minimally effected.

The above phenomena are not of concern if there is a big area of batteryelectrode, because the voltage of the system as a whole will not change.However, in the case of a small battery electrode, the transmitter canpotentially lower the voltage of the battery, and there will be a changein voltage over the entire circuitry. If the battery is divided into twoparts, the voltage of one battery can be changed while the other willcontinue to power the address generation circuit with a constantvoltage.

A consideration in the design development is how one battery will affectthe other. Experiments conducted by some of the present inventors showthat a change of load on one battery does not affect the other; i.e.,they worked independently. In this experiment, as is shown in FIG. 23,two copper iodine anode electrodes were provided with a magnesiumelectrode as a common cathode. These were connected to a zero-resistanceammeter, and performance was measured. One copper iodine electrode wasconnected through a 2.5 KΩ resistor, and the other through a 200 KΩresistor. All the electrodes are submerged in a pH 2 HCl solution atabout 37° C. The data derived from this experiment is shown in FIG. 24.The two copper iodine electrodes work independently of each other.

An ordinary skilled artesian will easily identify different materialsand configurations for the above device. The chemistry of this copperiodine and various manners of preparation will be understood or quicklydeveloped.

The surface preparation before the copper iodine is forming is ofinterest. One approach is to use copper wire embedded in epoxy. This canbe plated with electrolytic copper. After the copper is polarized insolution of potassium iodide, copper iodine is formed on the tip of theelectrode. Copper iodine can also be formed by chemically deposition.Other means are also available.

10 μm is a typical range for thickness of copper iodide to produce anadequate amount of electricity to accomplish the activity of the devicefor a 15 minute period. If less thickness is employed, the transmissionwill last a shorter time. Thus, the thickness of copper iodide isdetermined by the time required to produce electricity to provide theresults needed for a particular application. For several seconds oftransmission, less than 1 μm of copper iodide would be adequate. For onemicrosecond of transmission, a few nanometers of copper iodinethickness, such as in the range of about 10-100 nanometers, morespecifically, about 20-50 nanometers is sufficient.

It is to be understood that this invention is not limited to particularembodiments described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to be limiting, sincethe scope of the present invention will be limited only by the appendedclaims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the invention, subject toany specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present invention, representativeillustrative methods and materials are now described.

All publications and patents cited in this specification are hereinincorporated by reference as if each individual publication or patentwere specifically and individually indicated to be incorporated byreference and are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. The citation of any publication is for itsdisclosure prior to the filing date and should not be construed as anadmission that the present invention is not entitled to antedate suchpublication by virtue of prior invention. Further, the dates ofpublication provided may be different from the actual publication dateswhich may need to be independently confirmed.

It is noted that, as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentinvention. Any recited method can be carried out in the order of eventsrecited or in any other order which is logically possible.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

Accordingly, the preceding merely illustrates the principles of theinvention. It will be appreciated that those skilled in the art will beable to devise various arrangements which, although not explicitlydescribed or shown herein, embody the principles of the invention andare included within its spirit and scope. Furthermore, all examples andconditional language recited herein are principally intended to aid thereader in understanding the principles of the invention and the conceptscontributed by the inventors to furthering the art, and are to beconstrued as being without limitation to such specifically recitedexamples and conditions. Moreover, all statements herein recitingprinciples, aspects, and embodiments of the invention as well asspecific examples thereof, are intended to encompass both structural andfunctional equivalents thereof. Additionally, it is intended that suchequivalents include both currently known equivalents and equivalentsdeveloped in the future, i.e., any elements developed that perform thesame function, regardless of structure. The scope of the presentinvention, therefore, is not intended to be limited to the exemplaryembodiments shown and described herein. Rather, the scope and spirit ofpresent invention is embodied by the appended claims.

What is claimed is:
 1. A system for communicating information within abody of a patient, the system comprising: a first device comprising atransmitter configured to transmit a quasi-electrostatic signal to thebody of the patient; and a second device comprising a receiverconfigured to receive the transmitted quasi-electrostatic signal,wherein the receiver is configured to couple to the body of the patient;and wherein the quasi-electrostatic signal is transmitted between thefirst device and the second device via a conducting medium for thequasi-electrostatic signal.
 2. The system of claim 1, wherein thequasi-electrostatic signal is transmitted between the first and seconddevice within the body of the patient and wherein the body of thepatient is the conducting medium for the quasi-electrostatic signal. 3.The system of claim 1, further comprising at least one third device,wherein the at least one third device is configured to receive thetransmitted quasi-electrostatic signal via a quasi-electrostaticcoupling to the body of the patient, wherein the quasi-electrostaticsignal is received by the at least one third device within the body ofthe patient, and wherein the body of the patient is the conductingmedium for the quasi-electrostatic signal.
 4. The system of claim 1,wherein the quasi-electrostatic signal comprises an identifier of thefirst device.
 5. The system of claim 1, wherein the first devicecomprises a signal generating circuit coupled to a power supply, andwherein the signal generating circuit is configured to generate thequasi-electrostatic signal.
 6. The system of claim 5, wherein the signalgenerating circuit comprises an oscillator coupled to an antenna.
 7. Thesystem of claim 6, wherein the oscillator is configured to operate at afrequency such that a radiation field generated by the antenna has awavelength more than 10 times longer than a largest dimension of thebody.
 8. The system of claim 7, wherein the oscillator is configured tooperate at a frequency of about 10 MHz or less.
 9. The system of claim1, wherein the first device is an ingestible medical device.
 10. Thesystem of claim 1, wherein the first device is a pharmaceutical deliverydevice.
 11. The system of claim 1, wherein the first device comprises apower source.
 12. The system of claim 11, wherein the power sourcecomprises two dissimilar materials that are configured to provide avoltage potential difference when in contact with a conducting fluid.13. The system of claim 1, wherein the second device is configured totransmit a control signal to an effector located in the body.
 14. Acommunications device comprising: a power supply; a signal generatingcircuit coupled to the power supply and configured to generate a signal;and an antenna coupled to the signal generating circuit and configuredto transmit the signal via a quasi-electrostatic coupling to a patient'sbody.
 15. The communications device of claim 14, wherein the powersupply comprises a battery.
 16. The communications device of claim 14,wherein the power supply comprises: an antenna configured to receiveenergy from an energy source via a quasi-electrostatic coupling to thebody; and a converter circuit configured to convert the received energyto electrical power.
 17. The communications device of claim 14, whereinthe antenna comprises a pair of electrodes.
 18. The communicationsdevice of claim 14, wherein the signal generating circuit comprises anoscillator coupled to the antenna.
 19. The communications device ofclaim 18, wherein the oscillator is configured to operate at a frequencyof about 10 MHz or less.
 20. The communications device of claim 14,wherein the signal generating circuit comprises: a driver coupled todrive a time varying potential on the antenna; an oscillator having anoutput, wherein the driver is configured to receive the output of theoscillator; and a modulator configured to modulate a frequency or aphase of the output of the oscillator to encode information in thesignal.